KR20150143725A - Sustained-release formulations of colchicine and methods of using same - Google Patents

Abstract

A colchicine pharmaceutical composition for oral administration is provided once a day. The formulation includes a sustained-release component and an optional or quasi-solid component, and the composition can be selectively adjusted to release the active ingredient according to a predetermined or preferred release profile. Also provided is a method of treating or preventing a cardiovascular disease and / or an inflammatory disease in a mammalian subject, comprising administering the novel formulation described herein.

Description

≪ Desc / Clms Page number 1 > Sustained Release Formulations of Colchicin and Methods of Use Thereof &

                Cross-reference to related application

This application claims priority to U.S. Provisional Application No. 61 / 812,514, filed April 16, 2013, and European Patent Application No. 13194505.7, November 26, 2013, the entire contents of which are incorporated herein by reference in their entirety .

(-) - N - [(7S, 12aS) -1,2,3,10-tetramethoxy-9-oxo-5,6,7,9- tetrahydrobenzo [a] heptalene-7 -Yl] -acetamide is an alkaloid found in the extracts of Colchicum autumnale, Gloriosa superba and other plants. This substance is a microtubule-disrupting agent used in the treatment of conditions that can be treated, alleviated or prevented using anti-inflammatory drugs.

Colchicine is well recognized as a therapeutic agent for acute inflammation of Gouty Arthritis, Familial Mediterranean Fever (FMF), and Behcet's disease. It is also used to treat a number of inflammatory disorders that tend to have fibrosis. Recently, colchicine has been proposed as being useful in the treatment of cardiovascular diseases.

In particular, Colchicine has been presented as an option for acute pericarditis (Class IIa symptoms) as a first-line treatment option for recurrent pericarditis (Class I symptoms) in the European Guidelines for the Management of Pericardial Diseases 2004 (Maisch et al. al. , Guidelines on the Diagnosis and Management of Pericardial Diseases , Eur Heart J., 2004, 25, 916-928).

Imajio et al. ( Circulation 2005, 112 (13), 2012-2016) reported that 120 patients with acute pericarditis (idiopathic, viral, post pericardiotomy syndrome, and connective tissue disease) A randomized, open, randomized design trial with aspirin or conventional therapy with colchicine (1.0 - 2.0 mg on the first day, 0.5 - 1.0 mg / day over the next 3 months) It is effective in treating and preventing pericarditis. The primary goal was recurrence and the recurrence rate was significantly reduced from 32.3% in the colchicine group to 10.7% at 18 months (p = 0.004).

Furthermore, in the same group, colchicines have been shown to be effective after failure of existing therapies for acute pericarditis (Imazio et al ., Arch Intern Med , 2005, 165 (17), 1987-91). In a prospective, randomized, open design, 84 patients with primary recurrent pericarditis were treated with conventional or conventional treatment with aspirin alone or in combination with colchicine (1.0 - 2.0 mg on the first day, 0.5 - 1.0 mg / day ). The primary goal was recurrence and the recurrence rate was significantly reduced in the colchicine group (18 months, 24.0% versus 50.6% in the case of insured).

In addition, colchicine has been shown to be effective for the second prevention of recurrent pericarditis (Imazio et al ., Ann. Intern. Med ., 2011, 155 (7), 409-14). Colchicin has also been shown to lower response after pericardial pericarditis (Imazio et al., Am. Heart J. , 2011, 162 (3), 527-532; Meurin and Tabet, Arch. Cardiovasc. 2011, 104 (8-9), 425-427).

Colchicine was first evaluated in a prospective open-label randomized trial of colchicine versus placebo (1.5 mg / day) starting on day 3 postoperatively in 163 patients undergoing cardiac surgery for the therapeutic effect of syndrome after pericardial dissection (Finkelstein et al ., Herz , 2002 27, 791-194).

On the third day of surgery, 360 patients (average age 65.7 + 12.3 years, male 66%) were treated with either placebo or colchicine treatment group (1.0 mg / day on the first day, Double-blind, randomized trial randomized to receive half-dose 0.5 mg daily for 1 month with a body weight greater than 70 kg, and half-dose if less than 70 kg or maximum dose not met) (Imazio et al ., European Heart Journal , 2010, 31, 2749-2754).

In other experiments, colchicine efficacy against cardiovascular disease was also confirmed. In a prospective, random, observer-blinded endpoint design, 532 patients with stable coronary artery disease taking aspirin and / or clopidogrel (93%) and statin (95% (Nidorf et al ., JACC , 2013, 61 (4), 404-410) after randomly assigned to a non-colchicine non-administered group. This study showed that administration of colchicine 0.5 mg / day in addition to statin and other standard second-line prophylactic agents is effective in preventing the development of cardiovascular events in patients with stable coronary artery disease.

When treating gout, the recommended dose of COLCRYS ^® is 1.8 mg / day once or multiple times per hour. For adults with gout, treatment begins with a dose of 1.2 mg when the first sign of symptoms is present and 0.6 mg after 1 hour (Physician's Desk Reference, 68th ed., (2014)).

COLCRYS ^® is a quasi-square formulation. Side effects associated with COLCRYS ^® include, but are not limited to, nausea, vomiting, abdominal pain, diarrhea, hair loss, weakness, nerve impulses, severe anemia, decreased white blood cell counts and platelet depressions (Physician's Desk Reference, 68th ed., 2014).

The present invention solves this and other needs by providing a modified formulation of colchicine characterized by the sustained release of the active ingredient. The present invention also provides a form in which colchicine or a salt thereof is effectively administered in a day, thereby reducing the side effects of colchicine and improving patient compliance, as compared to the current or daily high dose oral colchicine formulations.

Aspects of the invention illustrated herein include colchicine or a pharmaceutically acceptable salt thereof; There is provided a sustained release formulation of colchicine as an active ingredient, comprising a delaying agent and at least one pharmaceutically acceptable excipient.

Aspects of the invention exemplified herein provide a method of treating and / or preventing a cardiovascular disease in an individual, comprising administering to the subject a therapeutically effective amount of a sustained release formulation of Colchicin.

Aspects of the invention exemplified herein provide a method of treating and / or preventing an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of a sustained release formulation of Colchicin.

Aspects of the invention illustrated herein include dissolving colchicine in an amount of 0.25-0.75 wt% of the total composition to produce a granulating agent; Adding a filler and a binder to Step A, and wet-granulating the mixture; Drying the wet granulate of Process B; Blending the dried granulate of step C with a retarder, a filler, a fluidizing agent and a lubricant; And compressing the final granulate of step D into tablets. ≪ Desc / Clms Page number 3 >

Aspects of the invention exemplified herein are shaped and compressed sustained release formulations comprising a colchicine combined with a matrix and excipients characterized by a long-term, sustained, slow, relatively constant incremental colchicine release of colchicin upon administration Wherein the total amount of excipient is effective to bind colchicine in the sustained release solid matrix and is at least 99% of the weight of the shaped and compacted composition.

Aspects of the invention exemplified herein may include sufficient amounts of colchicine to contain from about 0.25 to about 0.75% of the total composition, from about 10 to about 80% of the total composition of lactose monohydrate, from about 5 to about 50% About 5% to about 40% of the total composition of Retalac, from about 0.5% to about 5% of the total composition of the total composition, about 1% to about 30% of the total composition of the composition, 6mPa * s of hypromelose, The present invention provides molded and compressed colchicine sustained-release tablets prepared by wet granulation with excipients such as talc, talc, and excipients comprising about 0.5 to about 5 percent stearic acid of the total composition.

This patent or application contains one or more drawings made in color. An open publication of the present patent or patent application to which the colored drawing is attached will be provided to the secretariat by paying the application and necessary expenses.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the dissolution profile of a colchicine sustained release formulation comprising an exemplary delaying agent at 10%, 15% and 20%, respectively.
Figure 2 shows the dissolution profiles of colchicine sustained formulations containing an exemplary retarder at 30% and a tablet hardness of 50 N and 130 N, respectively.
Figure 3 shows the dissolution profile of a colchicine sustained-release formulation according to Figures 1 and 2;
Figure 4 shows the dissolution profile of a colchicine sustained formulation containing 0% of an exemplary retarder.

I. Definition

For purposes of the present invention, the term " colchicine "includes colchicine or all pharmaceutically acceptable salts thereof.

"Pharmaceutically acceptable" means generally safe, non-toxic, not biologically or otherwise undesirable, and suitable for human pharmaceutical use as well as veterinary use.

"Pharmaceutically acceptable salts" encompasses derivatives of colchicine wherein the colchicine is modified by preparing an acid or base addition salt thereof, and also pharmaceutically acceptable solvates, such as hydrates, and co-crystals of such compounds and salts (co-crystal). Examples of pharmaceutically acceptable salts include mineral or organic acid addition salts of basic moieties such as amines; An alkali or organic addition salt of an acidic residue; And combinations comprising at least one of the foregoing salts, but are not limited thereto. Pharmaceutically acceptable salts include non-toxic salts of colchicine and quaternary ammonium salts. For example, non-toxic acid salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; Other acceptable inorganic salts include metal salts such as sodium salts, potassium salts, cesium salts and the like; Alkaline earth metal salts such as calcium salts, magnesium salts and the like, and combinations comprising at least one of the foregoing salts. Pharmaceutically acceptable organic salts include those derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, Acetic acid, benzoic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC- (CH2) n-COOH, and the like; Organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt and the like; And amino acid salts such as arginate, asparaginate, glutamate and the like; And combinations comprising at least one of the foregoing salts; Organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt and the like; And amino acid salts such as arginate, asparaginate, glutamate and the like; And combinations comprising at least one of the foregoing salts. All forms of such colchicine derivatives, for example all crystalline, amorphous and polymorphic forms are included. Specific colchicine salts include colchicine hydrochloride, colchicine dihydrochloride, and co-crystals, hydrates or solvates thereof.

The "pharmacokinetic parameter" refers to the in vivo characterization of the active substance (or the metabolite or surrogate marker of the active substance) such as plasma concentration (C), Cmax, Cn, C24, Tmax and AUC . "Cmax" is the measured concentration in plasma of the active substance at the peak or peak concentration point. "Cmin" is the measured concentration in plasma of the active substance at the minimum concentration point. "Cn" is the measured concentration in plasma of the active substance at about n hours after administration. "C24" is the measured concentration in plasma of the active substance at about 24 hours after administration. The term "Tmax" means the time after the administration of the active substance until the measured concentration in the plasma of the active substance reaches a maximum. "AUC" is the area under the measured concentration curve in plasma of the active substance over time measured from one point to another. For example, AUC0-tau is the area under the plasma concentration curve for a time from 0 hours to t hours, where t may be a duration that can measure the plasma concentration for the individual formulation. AUC0-∞ or AUC0-INF is the calculated area under the plasma concentration curve for time from 0 h to infinity. In a steady-state study, AUC0-τ is the area under the plasma concentration curve during the dosing interval (ie, from time 0 to time τ (tau)) and tau is the length of the dosing interval. Other pharmacokinetic parameters include a parameter Ke or Kel, a terminal elimination rate constant calculated from a semi-log plot of the plasma concentration versus time curve; There is a t1 / 2 terminal elimination half-life calculated as 0.693 / Kel; CL / F is apparent total body clearance after administration calculated as total dose / total AUC-∞; Varea / F is the apparent total volume of distribution after administration calculated as total capacity / (total AUC∞ x Kel).

"Efficacy" means the ability of the active substance administered to a patient to exert a therapeutic effect on the patient.

"Bioavailability" means the degree or rate at which the active substance is absorbed into a living system or becomes available at a physiologically active site. For active agents that are intended to be absorbed into the bloodstream, the bioavailability data for a given formulation can provide an estimate of the relative fraction of the administered dose that is absorbed into the systemic circulatory system. "Bioavailability" may be specified by one or more pharmacokinetic parameters.

"Dosage form" means the unit of administration of the active substance. Examples of dosage forms include tablets, capsules, injections, suspensions, solutions, emulsions, creams, ointments, suppositories, inhalation forms, transdermal forms and the like.

Refers to a formulation in which about 80% or more of the pharmaceutical material is released in about 30 minutes or less.

In the present application, the enhancer ("enhancer") is defined as any non-pharmaceutically active ingredient that improves the therapeutic efficacy of the formulation.

"Sustained form" is defined herein as the release of a pharmaceutical substance in a continuous manner for an extended period of time.

"Long term" means a continuous period of at least about 1 hour, at least about 4 hours, at least about 8 hours, at least about 12 hours, at least about 16 hours, or at least about 24 hours.

The term "rate of release or release rate" or "rate of dissolution" of a drug, unless otherwise stated herein, refers to the amount of drug released from the dosage form per unit time, for example milligrams of drug released per hour (mg / hr) or the% of total drug dose released per hour. The drug release rate for a dosage form is typically measured as the in vitro drug release rate, i.e., the amount of drug released from the dosage form per unit time measured under appropriate conditions and the appropriate fluid. The rate of release referred to herein is determined by placing the dosage form to be tested in the medium in the appropriate solution tank. The aliquot of media collected at pre-determined intervals is then injected into a chromatographic system equipped with an appropriate detector to quantify the amount of drug released during the test interval.

Side effects are defined herein as the secondary and common adverse effects of the drug.

Terms such as " treating ", "treating "," treating ", "alleviating ", or" alleviating " Or prophylactic measures implementing the prophylactic and / or onset of the onset of a targeted pathological condition or disorder. Thus, an object requiring treatment may be an entity already having a disorder; Objects susceptible to failure; And individuals who must prevent the disorder. Beneficial or desirable clinical results include, but are not limited to, alleviation of symptoms, attenuation of disease severity, stabilized (i.e., non-attenuated) conditions of the disease, delay or slowing of disease progression, And (irrespective of whether or not it is detectable). "Therapy" may also mean prolonged survival compared to expected survival if untreated. Individuals in need of treatment include individuals who already have the condition or disorder, as well as those susceptible to the condition or disorder, or to which the condition or disorder should be prevented.

By "individual", "individual", "animal", "patient" or "mammal" is meant any entity, particularly a mammal, in which diagnosis, prognosis prediction or therapy is desirable. Mammalian objects include humans, livestock, farm animals and zoos, sports or pets such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, cows, bears and the like. The meanings of the terms "eukaryote", "animal", "mammal" and the like are well known in the art and can be derived, for example, from Wehner und Gehring (1995; Thieme Verlag). The present invention also contemplates treating animals that are economically, agriculturally or scientifically important. Scientifically important organisms include, but are not limited to, mice, rats, and rabbits. Agriculturally important animals include, but are not limited to, sheep, cows and pigs, for example cows and dogs can also be considered economically important animals. In one embodiment, the subject / patient is a mammal; In other embodiments, the subject / patient may be a mammal (e.g., a mammal such as a guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, Gibbon, sheep, cow, or pig); Most preferably, the individual / patient is a human.

II. Colchin

Below, colchicine used in accordance with the present invention will be described in detail. The chemical structure of colchicine (ChemID 2012) is as follows:

The chemical name of colchicine is N [5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy 9-oxobenzo [a] heptalen-7-yl], (S) ; Molecular formula C ₂₂ H ₂₅ NO ₆ ; CAS number 64-86-8.

Colchicin is a long-standing antiinflammatory agent in human medicine, used in the treatment of inflammatory diseases, most commonly hyperalgesia. It is a natural product that can be extracted from two plants belonging to the lily family, Colchicum autumnale and Gloriosa superba. Colchicine is a tricyclic alkaloid with a molecular weight of 399.437. The active ingredient colchicine and its pharmaceutical formulations are listed in various domestic and international pharmacopoeias, such as the US Pharmacopoeia (USP).

The positive effects of herbal sources in the treatment of rheumatism and swelling were first mentioned in about 1500 BC. Its use in gout was first mentioned about 1,500 years ago (Graham and Roberts, 1953, Ann Rheum Dis 12 (1): 16-9). Today, the therapeutic value of colchicines is well established in many inflammatory diseases and has been approved by the FDA as a preventive and therapeutic agent for acute gout flare and familial Mediterranean fever (FMF). Other major established but unapproved treatments include Behcet's disease and recurrent pericarditis. In the case of all known symptoms, this is generally administered orally as a solid tablet in a dose of 0.5-0.6 mg / tablet (e.g., European and US, respectively). Although the pharmacologic mechanism of action of colchicine in various disorders has not been fully elucidated, it is known that drugs are preferentially accumulated in neutrophils, particularly in neutrophils, which are important for their therapeutic effects. Three major interactions between colchicine and certain proteins modulate their pharmacokinetics: cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. The strongest therapeutic effect of the drug is believed to be related to its ability to bind to beta-tobuulin and inhibit self-granulation and polymerization of microtubules. The use of tubulin is essential for many cell functions such as mitosis. Thus, colchicines function effectively as "mitotic poisons" or parasitic poisons. Colchicine interferes with a number of cell functions participating in immune responses, such as the regulation of chemokine and prostaglandin production and the inhibition of neutrophil and endothelial cell adhesion molecules, by inhibiting self-assembly of microtubules. Ultimately, it reduces the degranulation, chemotaxis and phagocytosis of neutrophils, and lowers inflammation initiation and amplification. In addition, colchicine inhibits uric acid crystal deposition (which is an important process in the generation of gout), which is enhanced by the low pH in the tissues, presumably by oxidation inhibition of glucose and subsequent inhibition of lactate reduction in leukocytes (Imazio, Brucato et Eur J Intern Med, 21 (6): 503-8 ; Stanton, Gernert et al. 2011, Med Res. Rev. 2009, Eur Heart J, 30 (5): 532-9 ; Cocco, Chu et al. , 31 (3): 443-81). In the treatment of pericarditis, colchicine exerts its therapeutic effect by inhibiting acute pericardial inflammation. However, the cellular and molecular mechanisms by which Colchicine actually relieves pain and inflammation in acute pericarditis and prevents recurrence have not been fully elucidated.

In the present invention colchicine can be used for the prevention and / or treatment of cardiovascular diseases and / or inflammatory diseases.

III. Sustained-release formulation

The present invention additionally provides a sustained release colchicine formulation for treating or preventing a cardiovascular and / or inflammatory disorder in a subject, wherein the colchicine is released from the formulation at a constant rate according to a pre-defined or preferred release profile. This release is accomplished by incorporating the formulation into a facial form component and an optional quasi formal component. Colchicine formulations of the present invention may be formulated as tablets, pills, capsules, caplets, troche, sachets, cachet, pouches, sprinkles or other oral May be formulated in any form suitable for administration.

In the present invention, colchicine (i.e., in particular, (pharmaceutical) composition form) described herein is administered in the form of a sustained release formulation. Other expressions such as " multiple-effect type ", "controlled release type "," modified release ", or "delayed release "," preparation ", or " Herein, it is understood that it has the same meaning as the "sustained-release preparation ". These formulations may be in any form which can be imagined by those of ordinary skill in the art and may be in the form of oral (solid, semi-solid, liquid), skin (skin patch), sublingual, parenteral , Gel or ointment) or rectal (suppository) dosage forms as long as sustained release is ensured.

In the present invention, the sustained-release preparation encompasses all drug forms that establish a stable drug release profile that allows long-term drug substance availability after application to the patient. The long term may be at 10, 20, 30, 40, 50, or 60 minutes and at about 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17, 18, 19, 20, 21, 22, 23 or 24 hours. In addition, the response type may be 10, 20, 30, 40, 50, or 60 minutes and about 2,3, 4,5, 6,7, 8,9, 10,11, 12,13,14,15,16,17 , Is defined functionally as being released at 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99 percent (%) colchicine after 18, 19, 20, 21, 22, . The post-mortem form here can also be defined as colchicine being made available to the patient irrespective of absorption, since some colchicine can never be absorbed by the patient. Various forms of dosage forms can be readily designed by those skilled in the art to achieve delivery and sustained release of colchicine to the liver and / or small intestine and the large intestine.

In some embodiments, the sustained release formulation may be pH independent. This allows such formulations to be dissolved in almost any environment. In other embodiments, the sustained release formulation may be pH dependent. This allows release at a generally predictable location, which is at a greater distance from the lower intestine where the release delay is reached when not deformed. A method of delaying release is, for example, a coating. Any coating should be applied to a thickness sufficient to dissolve the entire coating in gastrointestinal fluids at a pH of greater than or equal to about 5 but not at a pH of less than about 5. Any anionic polymer exhibiting a pH-dependent dissolution profile is expected to be used as an enteric coating agent in the practice of the present invention to achieve delivery to the lower gastrointestinal tract. Polymers and mixtures thereof can be used to provide a delayed release or bioavailability of the active ingredient and coatings for some of its properties, including, but not limited to, a purified lac, which is obtained from the resinous secretions of insects Shellac that is a product. This coating dissolves in medium with pH> 7.

In some embodiments, sustained release formulations can be affected by the presence of alcohol in the body. The presence of alcohol in the patient's body may increase the dissolution of the composition and may cause immediate release of the total dose. This action is called "capacity dumping" and depends on the alcohol solubility of the material. In the case of sustained release formulations containing high doses for slow release over 24 hours, for example, this action may be a safety problem and life-threatening.

In order to achieve a uniform or sustained release rate, sustained release formulations may be formulated using time release hydrophilic matrices. Such time release hydrophilic matrices are well known in the field of drug formulation. For example, one such hydrophilic matrix is hydroxypropyl methylcellulose (HPMC) or hiropromelose. The hydrophilic matrix, in combination with the corrosion process, provides for an initial release of the drug product at an early stage, which is primarily triggered by rapid swelling of the surface of the matrix tablet, so that the drug substance distributed near the surface of the tablet is immediately released. In one embodiment, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, or about 10% Lt; / RTI > In one embodiment, at least about 20% of the drug substance can be released immediately. In other embodiments, at least about 20% of the drug substance may be released within the first about 30 minutes. As used herein, the term " about "or" approximately " means a 10% deviation in a labeled value (e.g., 50%, 45%, 40%, etc.), or in the case of a numerical range, Means the 10% deviation of For example, "about 50%" refers to a range of 45% to 55%. Upon initial swelling of the tablet surface, gel formation of the hydrophilic matrix is initiated. This gelation protects the core of the tablet from immediate dissolution and degradation, allowing the major part of the drug substance to slowly dissolve in the gel structure over time and diffuse into solution according to the principle of the peak. Diffusion itself can be triggered in this formulation mode through the viscosity of the formed gel, which is dictated by the concentration of hypromellose and the molecular weight of the hypromellose. Thus, the drug release profile can be modified by using multiple viscosity grades of hypromelose or a mixture thereof. All corresponding formulation and process parameters to achieve the expected release profile are well-known and can be tailored using actual development techniques, such as formulation screening, statistical design of experiments.

In one embodiment, a substance that is responsible for sustained release in the controlled-release formulation may be further admixed with the binder. Binders are added at the time of manufacture to increase the mechanical strength of the granules and tablets. The binder can be added to the formulation in various ways: (1) in the case of dry powders, it is mixed with the other components before wet flocculation; (2) as a solution, which is used as a flocculating liquid during wet flocculation; And (3) as a dry powder, which is mixed with other components before compaction. In this form, the binder is referred to as a dry binder. Solution binders are a common way to add binders to granules. In certain embodiments, the binder used in the formulation is in the form of a dry powder binder. Non-limiting examples of binders usable in the core include hydrogenated vegetable oils, castor oils, paraffins, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, fatty acid esters, wax-like materials such as fatty alcohols, Fatty acid glycerides, hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic polymers with hydrocarbon backbones, and mixtures thereof. Specific examples of water-soluble polymer binders include modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC) and hydroxypropyl cellulose (HPC), polyvinyl alcohol, and mixtures thereof . In one embodiment, the binder is HPMC. In another embodiment, the binder is a high promethose 6 mPa * s. In one embodiment, the binder may be present in an amount from about 1% to about 30% by weight of the formulation.

In another embodiment of the invention, the sustained release formulation may comprise a disintegrant. Disintegrants are used in the manufacture of pharmaceutical preparations of tablets, which upon dissociation of the tablet upon contact with moisture release the pharmaceutical preparations thereof. In one embodiment, the disintegrant may be water soluble to support the degradation of the tablet from above. Non-limiting examples of disintegrants for use in the formulation include sucrose, lactose, especially lactose monohydrate, trehalose, maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, Acid DVB, cross-linked PVP, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch, and mixtures thereof. In the implementation in one or more embodiment, the disintegrant is microcrystalline cellulose (e.g., Avicel PH101), cross-linked polyvinylpyrrolidone (e.g., KOLLIDON ^® CL), cross-linked sodium carboxymethyl cellulose (e.g., AC-DI-SOL (TM )), starch or starch derivatives such as sodium starch glycolate (e.g., EXPLOTAB ^®), or a combination of starch (for example, PRIMOJEL (TM)), swellable ion-exchange resins, such as AMBERLITE (TM) IRP 88, Formaldehyde-casein (e.g., ESMA SPRENG (TM)), and mixtures thereof.

In another embodiment of the invention, the sustained release formulation may comprise a filling agent or filler. Fillers refer to inert materials used as fillers to establish desired bulk, flow and compression characteristics in the preparation of tablets. Non-limiting examples of fillers for use in formulations include sucrose, lactose, especially lactose monohydrate, trehalose, maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, methacrylic acid DVB, cross-linked PVP, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch, and mixtures thereof. In one embodiment, the lactose monohydrate is included as a filler in a weight content of from about 10% to about 80%, preferably about 59%, of the formulation. In one embodiment, the pregelatinized starch is included as a filler in a weight content of from about 5% to about 50%, preferably about 7.5%, of the tablet.

In other embodiments, the sustained release formulations of the present invention may comprise a release agent to maintain a constant release rate of the drug. Examples of retarding agents include, but are not limited to, cellulose ethers, cellulose esters, acrylic acid copolymers, waxes, gums, glyceryl fatty acid esters and sucrose fatty acid esters. In one embodiment, the retarding agent is RETALAC (R) (Meggle), a blend of 15 parts of lactose monohydrate and 50 parts of hypromelose. The viscosity of the highromellose used herein may range from 6 mPa * s to 100,000 mPa * s. In one embodiment, the viscosity of the hypromelose used is 4000 mPa * s. By adjusting the amount of retardant in the composition, the release rate of the drug can be varied. In one embodiment, the formulation of a delaying agent in accordance with the present invention releases colchicine in a continuous and steady manner and is adjusted in such a way that about 80% of the active ingredient is released in vitro for a predetermined period of time. For example, as a non-limiting example of the invention, the duration may be up to 24 hours, up to 16 hours, up to 12 hours, up to 8 hours, up to 6 hours, up to 4 hours, up to 3.5 hours Or 1.5 hours or less. It is understood that the release rate may vary depending on whether the experiment is performed in vitro or in vivo. Thus, if the desired release rate is about 1.5 to about 3.5 hours in vitro or about 1.5 to about 6 hours in vitro, the release rate in vivo may actually vary depending on the experimental conditions. In one embodiment, the sustained release formulations of the present invention release colchicine in a continuous and consistent manner in such a way that about 80% of the active ingredient is released in vitro between about 1.5 to about 2.5 hours.

In other embodiments, the sustained release formulations of the present invention may comprise a glidant. The fluidizing agent can be used to improve the flow characteristics of the powder before and during tableting and to prevent cake formation. Suitable fluidizers include colloidal silicon dioxide, magnesium trisilicate, cellulose powder, talc, tribasic calcium phosphate, and the like. In one embodiment, the talc is included as a fluidizing agent in a weight content of from about 0.05% to about 5%, preferably about 1%, of the tablet.

In other embodiments, the sustained release formulations of the present invention may comprise a lubricant. The lubricant may be added to the pharmaceutical formulation to reduce any friction that may occur between the solid and die walls during tablet preparation. Strong friction during tableting can cause a series of problems such as deteriorating tablet quality (capping or even fragmentation of the tablet at the time of injection and vertical scrubbing of the tablet edge) and may even stop production. Thus, lubricants are added to certain tablet formulations of the invention, such as those of the specific formulations described herein. Non-limiting examples of lubricants usable in cores include glyceryl behenate, stearic acid, vegetable oils (e.g., STEROTEX®, hydrogenated soybean oil (STEROTEX® HM) and hydrogenated soybean oil & caster wax STEROTEX K), stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably 4000, and more), magnesium stearate, glyceryl monostearate, polyethylene glycol, ethylene oxide polymers , Union Carbide, Inc., Danbury, Conn.), Sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, mixtures thereof, And others. In one embodiment, the stearic acid is included as a lubricant in a weight content of from about 0.05% to about 5%, preferably about 1%, of the tablet.

In addition, sweeteners that may be used in a taste-masking coating of a particular matrix dosage form include glucose (corn syrup), dextrose, phosgene, fructose, and mixtures thereof (when not used as a carrier) ; Saccharin and its various salts such as sodium salts; Dipeptide sweeteners such as aspartame; Dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); Chloro derivatives or sucrose, for example sucralose; And sugar alcohols such as sorbitol, mannitol, xylitol and the like. Hydrogenated starch hydrolysates and synthetic sweeteners such as 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazine-4-1-2,2-dioxide, especially potassium salts acesulfame-K), and the sodium and calcium salts thereof. The sweeteners may be used alone or in any combination.

The controlled-release formulations of the present invention may also include one or more pharmaceutically acceptable excipients such as granulating or granulating agents, coloring agents, flavoring agents, pH adjusting agents, anti-adherents, fluidizing agents and similar excipients conventionally used in pharmaceutical compositions As shown in FIG. In one embodiment, the coloring excipient may advantageously be added to provide a visual change to prevent overdose. This can impart color to the liquid or particles simultaneously or independently of each other. Among the suitable coloring agents, the following substances may be mentioned: indigotine, cochineal carminic acid, yellow orange S, allura red AC, iron oxide, curcumin ( cucurmin, riboflavin, tartrazine, quinoline yellow, azorubine, amaranth, carmines, erythosine, red 2G, petalned blue V ( patented blue V), glittering blue FCF, chlorophyll, copper complex in leafy rock, green S, caramel, glittering black BN, carbo medicinalis Vegitable (such as vegetabilis, Brown FK and HT, carotenoids, Annatto extract, paprika extract, lycopene, lutein, canthaxanthin, beetroot red, anthocyane, calcium carbonate, titanium dioxide , Aluminum, silver, gold or litholrubin BK or any other coloring agent suitable for oral administration.

In one embodiment, the sustained release formulation may be coated. Coatings can provide a variety of functions. In some embodiments, a coating can be applied, for example, to achieve delayed release, acid tolerance, targeted release in the lower GI tract, and to avoid bad taste in the mouth. In some embodiments, a coating can be applied to protect the API / tablet from light and provide excellent mechanical resistance. Of course, it should be understood that the coating can provide other functions, and those skilled in the art are aware of the purpose of coating the tablet.

The pharmaceutical compositions and / or solid carrier particles may be coated with one or more enteric coatings, seal coatings, membrane coatings, barrier coatings, compression coatings, quick-disintegrating coatings or enzyme-degradable coatings. A plurality of coatings may be applied for desired performance. Further, it is contemplated that one or more of the active ingredients may be administered in combination with one or more of an immediate release, a pulsatile release, a controlled release, an extended release, a delayed release, a targeted release, May be provided for synchronized release or targeted delayed release. Indeed, formulations may contain conventional pharmaceutical active substances (e.g., pseudephedrin) and vitamins (e.g. vitamin C), minerals (Ca, Mg, Zn, K) or other supplements (e.g. St. John's Wort, echinacae, amino acids). For release / absorption control, solid carriers may be prepared with various component types and levels or thicknesses of coatings, with or without active ingredients. These various solid carriers can be blended into the dosage form to achieve the desired performance. Oral delivery is most commonly used, but liquid formulations are delivered by oral, nasal, ball, eye, urethral, transmucosal, vaginal, topical or rectal routes and may be manufactured for such routes.

When formulated with microparticles or nanoparticles, the drug release profile can be readily modified by the addition of a coating, such as a hard or soft gelatin coating, a starch coating, a resin or polymer coating and / or a cellulose coating. Although not limited to microparticles or nanoparticles (e.g., as in microcapsules or nanopascapsules), such dosage forms include, for example, seal coatings, enteric coatings, lotion coatings, or targeted delayed release coatings Can be additionally coated. The term "enteric coating" relates herein to a mixture of pharmaceutically acceptable excipients applied, combined with, mixed with, or added to a carrier or composition. The coating may be applied to the active ingredient to be compressed, shaped or compressed and may also include gelatin and / or pellets, beads, granules or particles of the carrier or composition. The coating may be applied after dissolution in an appropriate solvent, or through an aqueous dispersion. The carrier may or may not be fully or partially biodegradable.

In one embodiment, a polymethacrylate acrylic polymer may be used as the coating polymer. In at least one embodiment, the coating is an acrylic resin lacquer used in the form of an aqueous dispersion, such as that available under the trade name EUDRAGIT® from Rohm Pharma or the trade name KOLLICOAT® from BASF. In a more preferred embodiment, EUDRAGIT E100 is used as a coating polymer, which is a cationic copolymer based on dimethylaminoethyl methacrylate and neutral methacrylic esters with an average molecular weight of about 150,000. Various coating polymers of certain embodiments may be mixed in any desired proportions to obtain a coating with ultimately the desired drug dissolution profile. The coating method may consist of spraying the polymer solution onto the tablet in a pan coater or fluid bed coating apparatus. The solvent may be organic or aqueous depending on the nature of the polymer used. In a preferred embodiment, the solvent is an alcohol. Coating methods are well known in the art.

The composition of the present invention may also be formulated as a long-coated delayed-release oral dosage form, i.e., an oral dosage form of a pharmaceutical composition as described herein, using an intestinal coating to release from the lower gastrointestinal tract. The intestinally coated dosage forms will generally comprise microparticles, microgranules, micropellets or microbeads of the active ingredient and / or other compositional components, which are themselves coated or uncoated. The intestinally coated oral dosage form may also be a capsule (coated or uncoated) comprising pellets, beads or granules of the solid carrier or composition, either self-coated or uncoated.

The carrier for use herein comprises a permeable and semi-permeable matrix or polymer that controls the release characteristics of the formulation. Such polymers include, for example, cellulose diacylate, acetate and other semi-permeable polymers such as those described in U.S. Patent 4,285,987 (incorporated herein by reference) as well as U.S. Patent 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,142 (the relevant parts of which are incorporated herein by reference), and optionally polyunsaturated polymers formed by co-precipitation of polyanions.

Other carriers for use in the present invention include, for example, starch, modified starch and starch derivatives, gums, non-limiting examples of xanthan gum, alginic acid, other alginates, benitoniite, veegum, Guar, locust bean gum, gum arabic, quince psyllium, flax seed, okra gum, arabinoglactin, pectin, Crosslinked polyvinylpyrrolidone, ion-exchange resins such as potassium polymethacrylate, carrageenan (and derivatives), carrageenan (and derivatives), polyacrylonitrile, Gum karaya, biosynthetic gum, and the like. Other useful polymers include polycarbonates (linear polyesters of carbonic acid); Microporous materials (bisphenol, microporous poly (vinyl chloride), microporous polyamides, microporous modacrylic copolymers, microporous styrene-acrylic and copolymers thereof); Poly (alkylene sulfide), phenolic, polyester produced by esterification using an alkylene polyol of a polyol, a polyol, a polyol, a polysulfone, a porous poly (vinylidene), a polychloroether, an acetal polymer, a dicarboxylic acid or an anhydride , Asymmetric porous polymers, crosslinked olefin polymers, bulk density reduced hydrophilic microporous homopolymers, copolymers or interpolymers, and other similar materials, poly (urethanes), crosslinked chain-extended poly ), Poly (imide), poly (benzimidazole), collodion, regenerated protein, semi-solid crosslinked poly (vinylpyrrolidone).

The choice of additional additives and their levels, primary coating materials or materials, will depend on the following characteristics: the pH level of the target site, the desirability of making the tablet pH-dependent or pH-independent, Solubility, dissolution and disintegration resistance at the top; Impermeability of stomach fluid and drug / carrier / enzyme in stomach; The ability to rapidly dissolve or disintegrate in the target intestinal tract; Physical and chemical stability during storage; Non-toxic; Easy application as a coating (substrate affinity); And economical practicality.

In addition to the above, various formulations which illustrate the invention without limiting the scope of the invention are hereinafter described. Controlled release tablets or capsules etc. comprise colchicine as a core coated with the immediate release layer. Controlled-release, two-ply tablets or capsules, etc. include a sustained release layer and an immediate release layer. Controlled release tablets with three or more layers include (i) one or more layers of a material that controls slow release properties and (ii) one or more immediate release layers.

In one embodiment of the invention, the composition comprising colchicine is further coated with one or more release-releasing intermediate layers of an intermediate layer that is partially soluble to control the release of colchicine.

Traditionally, colchicine immediate-release dosage forms (mostly tablets, also injections or oral solutions) have been used to treat gout or FMF. Globally, all approved medicines containing colchicines are approved for ventilation and / or FMF only, which is a square tablet. Colchicine is used to prevent certain other inflammatory diseases, such as pericarditis, PPS, in patients with stable coronary heart disease in recent years. The difference between treatment and prophylaxis in colchicine is the treatment of obvious diseases and / or ongoing inflammation at the time of treatment. Therefore, colchicine is required at high concentrations, usually accompanied by unwanted side effects, most often gastrointestinal seizures. Prevention should not inhibit ongoing inflammation, but should inhibit inflammation. Therefore, colchicine requires an estimated but fixed level, which is beneficial. As described herein, this is accomplished by administering colchicine formulated as a sustained release formulation as described above.

In treating acute inflammatory diseases such as FMF or gout, high doses and high serum levels are essential, and inhibition of inflammation is desirable. Thus, conventional tablets that are rapidly released and have a rather low plasma half-life are suitable. However, in preventing cardiovascular disease, lower levels may be sufficient to inhibit neutrophil activity. The sustained-release system facilitates maintenance of the colchicine's more stable condition and reduces the occurrence of side effects.

The advantage of administering colchicine in a sustained manner, for example, is that the flattening of the serum level curves (low but broad peak levels) lowers serious side effects associated with colchicine toxicity, and also in the case of potential drug interactions It is. Much of the colchicine-related toxicity arises from the fact that one or both of the excretory pathways (liver and kidney) are deactivated by other drugs or by diseases (e.g., kidney failure). If the drug is absorbed in a slower and prolonged manner (the body fat), the body will spend more time extracting colchicine from the system. In this case, colchicine levels are less likely to reach toxic levels if there is a deficiency in emissions (due to drug interactions or disease). In addition, the sustained release of colchicine prevents dumping of the drug, so that dissolution of the composition is not significantly affected by alcohol.

Furthermore, sustained release prolongs the time that colchicine is present at the therapeutic level in the blood. As a result, disease progression is much more effectively inhibited, thereby improving clinical performance.

In addition, for the prophylactic use described herein, colchicine should not penetrate deeply into tissue (as in gout), which may be directly active in the blood system (blood vessels) and may cause plaque, particularly inflammatory blood cells (Neutrophils). This means that colchicine can be therapeutic even at lower total amounts and at serum levels. For example, rapid and high dose colchicine can be prevented, as in the case of treating acute gout deterioration. Thus, low doses of colchicine, e.g., about 0.1 to about 0.75 mg of sustained release formulation (or frequent dosing at lower doses), as described above, may be sufficient to achieve desirable clinical performance.

Under normal circumstances, most colchicine is absorbed in the small intestine and goes to the liver (some are excreted into the urine through the kidneys). Colchicine is metabolized in the liver, but a considerable proportion is not metabolized through the liver. That is, it goes to the bile through the liver, where it is excreted into the colon (colon). This can be reabsorbed back into the body, resulting in a characteristic secondary peak (reaching about 50% of the total amount of absorbed colchicine, which is thought to cause gastrointestinal problems such as diarrhea). If colchicine is formulated as a sustained-release preparation as described above, colchicine is slowly released and slowly reabsorbed. As a result, colchicine is metabolized more completely in the liver (at the same time, it is less likely to become busy with colchicine), thus lowering the recycle of uncollected colchicine. This results in a lower incidence of gastrointestinal problems. Colchicine administered in a sustained manner in accordance with the present invention may also be beneficial to other side effects / adverse effects associated with colchicine treatment / administration (those skilled in the art will recognize the side effects that may occur during colchicine administration or colchicine treatment has exist). Therefore, as described above, administration of Colchicin as a sustained release enhances safety and provides safety benefits.

IV. Manufacturing method of sustained-release formulation

The present invention relates to a process for the production of Colchicine formulations comprising a sustained-release component and an optional or quasi-curative component, wherein the colchicine is released from the formulation at a sustained rate according to a predetermined or preferred release profile do.

In one embodiment, the colchicine compositions described herein are in tablet form. As used herein, the term "tablet" means a compressed pharmaceutical dosage form of any type or size. The tablets described herein may be obtained from a composition comprising colchicine and a pharmaceutically acceptable excipient. Any colchicine composition may be in any of the other dosage forms known in the art, particularly any oral dosage form, e.g., in the form of a capsule.

In a first aspect of the invention, a controlled release formulation for use in an oral dosage form is provided. This formulation comprises a mixture containing a hypromellose as a hydrophilic matrix effective to provide controlled release of a pharmaceutically active ingredient.

Matrix systems are well known in the art. In a typical matrix system, the drug is uniformly dispersed in the polymer in combination with conventional excipients. This mixture is typically compressed and compressed into tablets. The API is released from the tablet by diffusion and corrosion. The matrix system comprises (i) a Handbook of Pharmaceutical Controlled Release Technology, Ed. D. L. Wise, Marcel Dekker, Inc. New York, N.Y. (2000), and (ii) Treatise on Controlled Drug Delivery, Fundamentals, Optimization, Applications, Ed. A. Kydonieus, Marcel Dekker, Inc. New York, N.Y. (1992), the contents of which are incorporated herein by reference.

When the tablet is exposed to the aqueous medium in the gastrointestinal tract, the surface of the tablet becomes wet and the polymer begins to partially hydrate to form an outer gel layer. This outer gel layer is sufficiently hydrated and begins to corrode with aqueous body fluids. Water continues to penetrate into the core of the tablet and another layer of gel is formed in the layer below the outer gel layer to be dissolved. These successive concentric circular gel layers cause the API to be constantly released by diffusion through the gel layer and exposure through refining corrosion. In the case of mixtures of the present invention, when contained in a compression tablet matrix, the hygrometroses provide a hydrophilic swellable structure that can function as a gel layer. In this way drug release is controlled.

In one embodiment, colchicine formulations of the present invention can be prepared by wet or dry granulation of colchicine compositions, blending of the prepared granules and excipients, and compression of the composition into tablets.

In one embodiment, wet granulation is used to produce a wet granulate comprising colchicine. The granulating liquid is used in the wet granulation process. Both aqueous and non-aqueous liquids can be used as granulating liquids. In one embodiment, the granulating liquid is an aqueous liquid, or more specifically, purified water or deionized water. The content of the granulating liquid to be used may be determined depending on a number of factors, for example, the type of granulating liquid, the amount of granulating liquid used, the type of excipient used, the nature of the active material and the amount of active material loaded.

In one embodiment, the colchicine particles and the appropriate excipient are mixed with the granulation liquid for a sufficiently long period of time to ensure that all starting materials are well dispersed and well-contained uniformity. The wet granulation is generally carried out at a temperature of from about 20 ° C to about 35 ° C, more specifically at room temperature (about 25 ° C). After the wet granulation, the granules are dried at an elevated temperature to obtain dried granules. In one embodiment, the drying step can be performed long enough to reach the desired residual wetting. In one embodiment, it may be about 12-48 hours at about 45 < 0 > C. It should be understood that the total time to perform the granulation process can be determined by various factors such as, but not limited to, the solvent used, the size of the batch, the device used, and the like.

In order to contact the colchicine and the excipient with the granulating liquid, any device which achieves a uniform dispersion of the granulating liquid may be used. For example, small-scale production can be accomplished by mixing colchicine and excipients in a mortar or stainless steel ball, followed by mixing and wetting, and on a large scale, the V-blender is mixed with an intensifier fire bar, a planetary mixer, It can be used with high shear granulators and fluid bed granulators. In one embodiment, the granulator is a high shear granulator.

In one embodiment, a method of making a colchicine composition comprises wet granulating colchicine with a pharmaceutically acceptable excipient and a granulating liquid, and mixing the granulate with a second excipient in the next step to obtain a colchicine composition . In one embodiment, the pharmaceutically acceptable excipient comprises a binder and a filler. In one embodiment, the binding agent can be a high promoose. In one embodiment, the filler may be lactose monohydrate and pregelatinized starch. In another embodiment, purified water is used as the granulating liquid. In one embodiment, the second excipient to be mixed with the granulate may be a filler. In one embodiment, the filler may be lactose monohydrate. The colchicine composition may comprise from about 0.1 wt% colchicine to about 10 wt% colchicine, more specifically from about 0.25 wt% to about 0.75 wt%, based on the total weight of the colchicine composition.

In one embodiment, a method of making a composition comprises wet granulating colchicine and a pharmaceutically acceptable excipient to obtain a wet granulate, and mixing the granulate with a filler to obtain a colchicine composition . In some embodiments, the method further comprises drying the mixture. In another embodiment, the wet granulate is dried to obtain a dried granulate, and then the dried granulate is mixed with a binder, filler or both to obtain a composition. In other embodiments, the dried granulate may be milled to obtain a milled granulate, and then the milled dried granulate may be mixed with the binder, filler, or both. The method may further comprise mixing the colchicine composition with a fluidizing agent, a lubricant, or both, to obtain a blend, or to compress the blend to obtain a tablet. In one embodiment, the fluidizing agent may be talc. In other embodiments, the lubricant may be stearic acid. The method may further comprise a step of coating the tablet.

In another embodiment, a method of making a colchicine tablet comprises wet-granulating colchicine and a pharmaceutically acceptable excipient to obtain a wet granulate; Drying the wet granulate to obtain a dried granule; Milling the dried granulate to obtain a milled granulate; Mixing said milled granulate with total gum to obtain a composition; Mixing the composition with a fluidizing agent, a lubricant, or both to obtain a blend; And compressing the blend to obtain a colchicine tablet of the present invention.

In some embodiments, the wet granulation is dried to obtain a dried granulate, which is then mixed with a second excipient, such as a filler. The wet granulate may be dried by any suitable means for removing the granulating liquid to obtain a dried granulate comprising colchicine and a pharmaceutically acceptable excipient. The drying conditions and duration are determined by factors such as the weight of the liquid used and the weight of the granular particles. Examples of suitable drying methods include, but are not limited to, tray drying, forced air drying, microwave drying, vacuum drying and fluid bed drying.

After drying, the dried granulate may be mixed directly with excipients, for example fillers, binders or lubricants, for further processing. As another example, the dried granulate may optionally undergo further processing steps prior to mixing with the excipient. For example, dried granules can be sized before mixing with excipients to reduce particle size. Examples of sizing operations include milling or sieving. Any titration apparatus for reducing the size of the particles may be used in the present invention.

Suitable excipients may be added after granulation and mixed with the granulate to form a colchicine composition. As used herein, the term " extragranularly "or" extragranularly "means that the materials mentioned, for example, suitable excipients, are added or added as a dry ingredient after the wet granulation step . In one embodiment, the filler, binder, fluidizing agent, and lubricant are added to and mixed with the granules after granulation to form a blend. The blend can be directly encapsulated in a capsule cell, such as a hard gelatin cell, to produce a capsule formulation. As another example, the blend can be compressed into tablets. In some embodiments, the granulate is a dried granule or a milled dried granule.

The mixing can be carried out for a sufficient time to produce a homogeneous mixture or blend. The blending can be accomplished by any other method for obtaining blending, stiffing, shaking, tumbling, rolling or homogenous blends. In some embodiments, the ingredients to be mixed are combined under low shear conditions in a titration device such as a B-blender, tote blender, double cone blender or any other device that can act under low shear conditions.

The homogeneous mixture or blend is then compacted using any method suitable for the art. The mechanical force will define the physical properties of the tablet, particularly the crushing strength of the tablet being manufactured. The mechanical strength correlates with the initial swelling of the tablet and the dilution rate of the tablet core. This action is well known in the art and can be adjusted and controlled during the life cycle of the product. In the case of the colchicine sustained-release formulation of the present invention, the compressive strength used may range from about 30 N to about 130 N. In one embodiment, the compressive strength may be about 100N. In other embodiments, the compressive strength may be about 100 N +/- 15N.

Colchicine tablets prepared in the manner described above exhibit acceptable physical characteristics such as good friability and hardness. According to the EP and USP guidelines, the colchicine tablets described herein have a phoshicity ranging from about 0% to less than about 1%.

Colchicin tablets may be coated. The coating of the tablets can be carried out by any known method. Coatings for the colchicine tablets described herein may be any suitable coating such as, for example, a functional or non-functional coating or a plurality of functional or non-functional coatings. By "functional coating" is meant a coating that modifies the release properties of the overall formulation, e. G., A sustained-release coating. By "non-functional coating" is meant a coating that is not a functional coating, e. G. A cosmetic coating. Non-functional coatings may have some effect on the release of the active material due to initial dissolution, hydration, perforations, etc. of the coating, but will not be considered as significant differences relative to the non-coating composition.

In one embodiment, the colchicine composition comprises colchicine, a binder, a filler, a retarder, a fluidizing agent, and a lubricant. In one embodiment, the colchicine composition comprises about 0.25 to about 0.75 mg colchicine; About 10 to about 80 mg of lactose monohydrate; About 5 to about 50 mg of pregelatinized starch; About 1 to about 30 mg of hypromelose 6 mPa * s; About 5 to about 40 mg of Retalac (4000 mPa * s 50/50 w / w% lactose monohydrate and hiropromellose); About 0.5 to about 5 mg of talc; And about 0.5 to about 5 mg of stearic acid. In one embodiment, the colchicine composition comprises about 0.5 mg of colchicine, about 59 mg of lactose monohydrate; About 7.5 mg pregelatinized starch; About 1 mg of hypromelose 6 mPa * s; About 30 mg of Retalac (lactose monohydrate and 4000 mPa * s 50/50 w / w% of hyprogramolose); About 1 mg of talc; And about 1 mg of stearic acid. The colchicine dosage form has a total weight of about 100 mg. The colchicine composition may be in tablet form.

V. Therapeutic methods using saliva colchicine

The present invention also relates to a method for the treatment of cardiovascular disease and / or cardiovascular disease in a subject, comprising the step of administering a colchicine formulation of the present invention to a subject in a therapeutically effective amount, wherein the colchicine is released from the formulation at a sustained rate according to a pre- Lt; RTI ID = 0.0 > inflammatory < / RTI > disorder. The method of the present invention has the flexibility to selectively adjust the pharmacokinetics of the formulations to be administered according to the nature of the condition and the needs of the patient due to the new colchicine formulation design which includes the anti- The emission profile of the quantum components can be selectively modified during the fabrication process described above to achieve a predetermined emission profile.

In one embodiment, the treatment comprises application or administration of a colchicine formulation as described herein, wherein the patient is suffering from or at risk of developing a cardiovascular disease and / or inflammatory disorder. In another embodiment, the treatment is also intended to include the administration or administration of a pharmaceutical composition comprising a colchicine formulation to a patient, wherein the subject is suffering from or at risk of developing cardiovascular disease and / or inflammatory disorder.

As used herein, the term "cardiovascular disease" refers to any disease that manifests itself in the heart and / or vascular system (all blood vessels such as arteries, capillaries and veins). This includes all diseases listed in Chapter 9 "Circulatory Diseases (I00-I99)" of the International Statistical Classification, 10th edition (ICD-10) version of the 2010 International Symposium on Diseases and Related Health Problems.

More specifically, all the diseases of this ICD-10 class involve a) inflammation of any part of the heart or blood vessels, as well as ischemia / atherosclerosis / hypertrophy of any vessel of the circulatory system.

Colchicin referred to herein is for use in treating and / or preventing any inflammatory disorder that occurs in cardiac tissue selected from ICD-10 sections I00-I99. More specifically, this includes acute and recurrent pericarditis as well as post-operative complications (postcardis syndrome, post-pericarditis syndrome, pericardial effusion) with inflammation of the pericardium. Other types of inflammatory heart disease include any form of myocarditis, endocarditis, and atrial fibrillation.

The mechanism of action suggested by these symptoms is inhibition of plaque instability by neutrophil inhibition. In stable coronary artery disease, fatty substances accumulate in blood vessels and form stable plaques. This plaque can be targeted by neutrophils. This can lead to plaque instability and, therefore, can lead to stable plaques and clinical events. Thus, the colchicines described herein can be used in the treatment of any of the ischemic conditions associated with ischemia, atherosclerosis and / or hypertrophy, which are caused by plaque formation of blood vessels (arteries, capillaries, veins) For the treatment and / or prevention of cardiovascular diseases. All diseases classified as ICD-10 sections I00-I99 that meet any of these requirements are claimed. Examples include stable coronary artery disease, cardiovascular atherosclerosis and atherosclerosis of the peripheral vascular system, abdominal aortic aneurysm (AAA), and carotid and iliac femoral / renal atheroma (eg, I25, I70).

In the context of the present invention, in patients with stable cardiovascular disease, acute cardiovascular disease is preferably a cardiovascular condition in patients with stable coronary artery disease.

In the context of the present invention, the terms "stable coronary artery disease" and "stable coronary heart disease" have the same meaning and are used interchangeably. Both terms include medical condition stable coronary artery disease (SCAD). In the terms "stable cardiovascular disease "," stable coronary artery disease ", or "stable coronary heart disease "," stable "is defined as any symptom that is diagnosed as cardiovascular disease without acute cardiovascular disease. Thus, for example, stable coronary artery disease is defined as another evolutionary phase of coronary artery disease, except in situations where coronary artery thrombosis is overwhelming clinical signs (acute coronary syndrome).

In the context of the present invention, colchicine may be used for the prevention and / or treatment of cardiovascular diseases. Cardiovascular diseases include, but are not limited to, heart disease as described, for example, in Robbins and Cotran, Pathologic Basis of Disease, Eighth Edition, Saunders Elsevier. Cardiovascular disease refers to a group of circulatory diseases such as heart, blood, and lymphatic ducts. Particularly, cardiovascular diseases may include vascular diseases accompanied by atherosclerosis, plaque formation or deposition. The most common cardiovascular diseases are coronary heart disease and stroke. Non-limiting examples of cardiovascular diseases that can be prevented or treated according to the present invention include coronary heart disease (a disease of the blood vessels that maintain myocardium), cerebrovascular disease (blood vessel disease that sustains the brain), peripheral arterial disease (Coronary and refractory membrane damage due to rheumatic fever caused by Streptococcus bacteria), congenital heart disease (deformed heart structure present at birth), heart Hypertension, hypertension, coronary artery disease, atherosclerosis, ischemic disease, abdominal aortic aneurysm, aneurysmal disease, and atherosclerosis. Carotid and iliac femoral / renal atheroma, heart failure, heart failure, arteriosclerosis, heart attack, and stroke. Heart attack and stroke are generally acute conditions and are caused primarily by blockage of blood flow to the heart or brain. The most common cause of this is the accumulation of fatty deposits on the inner walls of blood vessels supplied to the heart or brain. In addition, a stroke can be induced in the brain from blood vessel bleeding or blood clotting.

In particular, in the context of the present invention, colchicine has been implicated in acute pericarditis, recurrent pericarditis, recurrent pericarditis, post-pericardial syndrome (PPS), PPS in patients undergoing cardiac surgery and stable coronary artery (heart) May be used to prevent cardiovascular disease in patients with the disease (cardiovascular conditions may be acute cardiovascular events).

Pericarditis is an inflammatory disease that occurs in the pericardium, a fibrous elastic tissue cyst that consists of two thin layers surrounding the heart. The inflammation causes the pericardium to swell. As a result, rubbing against the sac heart causes chest pain, the most common symptom of pericarditis. Pericarditis is the most common form of inflammatory disorders of the heart, which is very rare in the population. Pericarditis is very heterogeneous in terms of its origin, clinical symptoms, and symptoms. It may be caused by local clinical problems or by systemic disease symptoms. In most cases (90%), pericarditis is an idiopathic (spontaneous, unknown) etiology, but it may also occur secondary to systemic infection, acute myocardial infarction, or autoimmune disease. Post-pericardial syndrome (PPS) may be a post-cardiac complication that occurs within a few days to a few weeks after surgery. The estimated incidence of the syndrome is relatively wide and appears in 10 to 40% of patients undergoing cardiac surgery (Prince and Cunhe, 1997, Heart Lung , 26: 165).

Non-limiting examples of (acute) cardiovascular pathologies include damage to the atherosclerotic wall, acute coronary syndromes, out-of-hospital cardiac arrest or non-cardiac ischemic stroke. Further, these conditions are described, for example, in Robbins and Cotran, Pathologic Basis of Disease, Eighth Edition, Saunders Elsevier.

In one embodiment, the colchicine formulations of the invention can be used to treat inflammatory diseases other than those described above. In one embodiment, inflammatory diseases include, but are not limited to, gout, familial Mediterranean fever, Behcet's disease, senile macular degeneration, and Alzheimer's disease.

Patients / individuals who are suffering from the aforementioned diseases and / or are suitable for treatment with colchicine according to the present invention can be diagnosed by routine and / or routine procedures. Those skilled in the art are well aware thereof. Diagnosis is also described, for example, in Robbins and Cotran, Pathologic Basis of Disease, Eighth Edition, Saunders Elsevier.

In one embodiment, the colchicine formulations referred to herein are useful for treating a variety of cardiovascular and / or inflammatory disorders. In some embodiments, the treatment of a cardiovascular disease and / or an inflammatory disorder is intended to include the amelioration, amelioration, attenuation of severity, or reduction of time of a disease, disorder, or condition, or any of its parameters or symptoms. In one embodiment of the invention, the term " disorder ", "disease" or "condition" is understood as a cardiovascular disease and / In the context of the present invention, "mitigation" refers to any observable beneficial effect, without limitation.

In the present invention, the colchicine formulations herein may be used to promote a positive therapeutic response in relation to cardiovascular disease and / or inflammatory disorders. A "positive therapeutic response" associated with a cardiovascular disease and / or inflammatory disorder may include, for example, delaying the onset of clinical symptoms of a disease or metamorphosis, alleviating the severity of some or all clinical symptoms of the disease or condition, , Improvements in overall health or well-being of the subject, or other parameters well known in the art that are specific to a particular disease.

In another embodiment, the colchicine formulations referred to herein are useful for preventing various cardiovascular and / or inflammatory disorders. In the context of the present invention, the term "prevention" is well known in the art. For example, a patient / individual suspected of being vulnerable to the disorder or disorder mentioned herein may be particularly beneficial in preventing the disorder or disease. The subject / patient may have susceptibility to or susceptibility to a disorder or disease, such as, but not limited to, hereditary scandal. Such sweeps can be determined, for example, by standard assays using genetic markers or phenotypic indicators. It is understood that the disorder or disease to be prevented according to the present invention is not diagnosed or diagnosed in the patient / individual (e.g., the patient / individual does not exhibit any clinical or pathological symptoms). That is, the term "prevention" includes the use of a compound of the invention before any clinical and / or pathological condition is diagnosed or measured, or before a primary care physician can diagnose or confirm. Prevention includes, but is not limited to, prevention of the onset of a disease or condition (prophylactic treatment) in a patient and / or individual who may not yet experience or display the symptoms of the disease, but may be susceptible to the disease.

Colchicin in accordance with the present invention may also be used in combination with conventional therapies for any of the diseases described herein. Such conventional therapies are well known in the art, and those skilled in the art are aware of all such therapies. The colchicines described herein can also be used in combination with colchicine-incompatible statins. In general, non-limiting examples of such statins include atorvastatin (Lipitor®, Torvast®), fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®, Altoprev®) , Pitavastatin (Livalo®, Pitava®), pravastatin (Pravachol®, Selektine®, Lipostat®), rosuvastatin (Crestor®) and simvastatin (Zocor®, Lipex ®). In conjunction with the present invention, colchicine-incompatible statins are used. Preferably, in the context of the present invention, the combination of a composition of the present invention and colchicine-incompatible statins is achieved in stable coronary heart disease. Such statins preferably do not interfere with, or only marginally interfere with, the action, metabolism and / or elimination mechanism of colchicine, due to its action, metabolism and / or cleavage mechanism, It is a statin that shows the risk of occurrence, severity and / or incidence of the onset of drug side effects.

In one embodiment, the use of colchicine is a fixed combination or an unfixed combination (within the same pharmaceutical formulation). "Fixed combination" should be understood to mean that the active ingredients of the combination are combined into a fixed dose in the same vehicle (single formulation) delivered together at the site of application. A fixed combination may mean, for example, a single form of a tablet, solution, cream, capsule, gel, ointment, salve, patch, suppository or transdermal delivery system. A "non-fixed combination" should be understood herein as meaning that the active ingredients / ingredients are contained in at least two vehicles (e.g., tablets, solutions, creams, capsules, gels, ointments, salves, patches, Or transdermal delivery system). Each vehicle may contain a desired pharmaceutical composition or active ingredient. For example, a preferred non-fixed combination referred to herein means that one vehicle contains the colchicines mentioned herein, and the other vehicle contains the colchicine-incompatible statins mentioned herein. Examples of fixed or non-immobilized combination (s) of colchicine mentioned herein include a combination of colchicine-incompatible statins and colchicines selected from the group consisting of atorvastatin, rosuvastatin, simvastatin and pravastatin. Specifically, a fixed or non-fixed combination of colchicine herein is understood to mean a combination of colchicine and atorvastatin. In particular, a fixed or non-fixed combination of colchicine herein is understood to mean a combination of colchicine and rosuvastatin. Specifically, a fixed or non-fixed combination of colchicine herein is understood to mean a combination of colchicine and simvastatin. Specifically, a fixed or non-fixed combination of colchicine herein is understood to mean a combination of colchicine and pravastatin.

In some embodiments, the colchicines mentioned herein can be used in combination with statins and other substances, for example in combination with ezetimibe / simvastatin. Colchicine herein can be used in combination with other drugs, such as those known to those skilled in the art and used in medicine (e.g., antibiotics, NSAIDs (non-steroidal antiinflammatory agents), corticosteroids).

VI. Method of administration

Methods of administering colchicine formulations of the present invention to a subject in need thereof are well known or readily determinable by one skilled in the art. The route of administration of the colchicine formulation may be, for example, oral, parenteral, by inhalation or topically. The term parenteral as used herein includes, for example, intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, rectal or vaginal administration.

When used as a composition in the context of the present invention, colchicin may comprise one or more pharmaceutically acceptable carriers and may thus be formulated in the form of topical formulations for administration thereof. Pharmaceutically acceptable carriers may include saline, sterile water, linger liquid, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more thereof, , And if necessary, additives such as an antioxidant, a buffer, a bacteriostatic agent, and the like. It is further contemplated that the diluents, dispersing agents, surfactants, binders and lubricants may be present in the form of topical preparations such as ointments, creams, gels, skin emulsions, skin suspensions, patches or sprays, May be added at the time of manufacture.

Non-limiting examples of administration of the compounds and / or compositions according to the present invention include, but are not limited to, coatings and non-coated tablets, soft gelatine capsules, hard gelatine capsules, lozenges, troches, solutions, emulsions, suspensions, Syrups, elixirs, reconstitution powders and granules, dispersing powders and granules, medicated gums, chewing tablets and effervescent tablets. The compositions according to the present invention may be administered orally (e.g., solid, semi-solid, liquid), skin (e.g., skin patch), sublingual, parenteral (e.g., infusion), eye (e.g., eye drops, E. G., Suppository). ≪ / RTI > In one embodiment, the compositions are formulated as tablets, capsules, suppositories, dermal patches or sublingual formulations.

The pharmaceutical composition used in the present invention may be, for example, a serum protein such as ion exchanger, alumina, aluminum stearate, lecithin, human serum albumin, a buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, Of water, a salt or an electrolyte such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based A pharmaceutically acceptable carrier such as polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and wool fat.

The particular pharmaceutical composition for use in the present invention may be orally administered in an acceptable dosage form such as, for example, capsules, tablets, aqueous suspensions or solutions. In addition, certain pharmaceutical compositions may be administered by nasal aerosol or by inhalation. Such a composition may be prepared as a solution in saline using benzyl alcohol or other corrective agents, absorption enhancers to enhance bioavailability, and / or other conventional solubilizing agents or oxidizing agents.

The amount of colchicine formulations in preparing a single dosage form in combination with a carrier material will vary depending upon the host treated and the particular mode of administration. The composition may be administered as a single dose, multiple doses or as an infusion for an established period of time. In addition, the dosage regimen may be adjusted to provide the optimal desired response (e. G., Therapeutic or prophylactic response).

In some situations, the compositions of the present invention may be administered parenterally. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents include vegetable oils such as propylene glycol, polyethylene glycol, olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include, for example, water, alcoholic / aqueous solutions, emulsions or suspensions, such as saline and buffered media. In the present invention, pharmaceutically acceptable carriers include, but are not limited to, phosphate buffer 0.01-0.1 M, preferably 0.05 M, or 0.8% saline. Other common parenteral vehicles include sodium phosphate solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Intravenous vehicles include fluid and nutrient supplements, electrolyte supplements, such as those based on Ringer ' s Dextrose, and the like. Preservatives and other additives such as antimicrobials, antioxidants, chelating agents and inert gases may also be present.

The parenteral formulation may be a bolus dose, infusion or loading bolus followed by a maintenance dose. These compositions may be administered at fixed or variable intervals, e. G. Once daily or "as needed ".

The composition according to the present invention may be administered in a dose range depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, emesis rate and severity of disease. As a compound itself for use as pharmacophores or pharmaceutical compositions, the compounds of the present invention may be administered to patients and / or individuals in an appropriate dose. Dosage regimens will be determined by the primary care physician and clinical factors. As is well known in the medical arts, the dosage for any one patient will depend upon a number of factors, including the patient's body size, body surface area, age, the specific compound administered, sex, timing and route of administration, overall health status, And is determined according to the factors of. In general, the dosage regimen for administering a pharmaceutical composition, including those defined herein, should be within the range, for example, as described below. Progress can be monitored by periodic evaluation.

The composition according to the invention may be administered as a single dose or as a 2, 3, 4, 5, 6, 7, 8, 9 or 10 dose, if appropriate. The composition may be administered at 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times a day. Preferably, colchicine according to the present invention is administered once a day. More preferably, colchicine according to the present invention is administered as a single dose once a day.

The composition according to the present invention can be administered regularly for a long period of time. In one embodiment, the composition may be administered periodically for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more. In other embodiments, the composition may be administered periodically for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer periods. As used herein, the term "periodically" means administration of the composition at a predetermined frequency or interval for a period of time. For example, the composition may be administered to the patient once per day for three years. In another embodiment, the composition can be administered to the patient once every two days for five years. The frequency of administration should be understood to depend on a number of factors, including, but not limited to, the severity of the disease, the overall health of the patient, any additional drugs the patient is taking, and whether the treatment is prophylactic or not. It should also be understood that the frequency of administration can be varied at any time.

The content / concentration / dose of the composition according to the present invention is 0.1 mg to 5.0 mg, 0.1 mg to 2.0 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1.0 mg, 0.1 mg to 0.75 mg, 0.1 mg to 0.5 mg, 0.25 mg - 0.25 mg - 2.0 mg, 0.25 mg - 1.5 mg, 0.25 mg - 1.0 mg, 0.25 mg - 0.75 mg or 0.25 mg - 0.5 mg. In one embodiment, a composition according to the present invention is administered at a daily dose of about 0.1 mg to about 0.75 mg or about 0.1 mg to about 0.5 mg of colchicin. In another embodiment, a composition according to the present invention is administered at a daily colchicine dosage of about 0.25 mg to about 0.75 mg or about 0.25 mg to about 0.5 mg. In one embodiment, the composition according to the invention is administered at a daily colchicine dosage of about 0.5 mg.

In a preferred embodiment, the colchicine content / concentration used herein is such that the dose on the first day of administration may be higher (concentration / content) than the colchic dose (maintenance dose / administration dose) administered on the next day (s) . As another example, this reduced dose (retention dose) may be initiated 2, 3, 4, 5, 6, 7, 8, 9 or 10 days after the first dose of high dose. If the course of treatment is as described above, the high dose / concentration / concentration of colchicine (on the first day of administration) may be any of the above, as long as the storage capacity (volume / volume of colchicine on the day following administration of high dose / / Concentration) is lower than the first (the first day of administration) dose / concentration / concentration of colchicine. Preferably, the composition of the present invention is administered at a dose of about 1.0 mg to about 2.0 mg (preferably one dose) of colchicine on the first day of administration and about 0.5 mg to about 1.0 mg of colchicine storage on the day following administration.

Consistent with the scope of the present invention, the Colchicine formulations of the present invention can be administered in a human or other animal according to the above-described methods of treatment in an amount sufficient to effect the therapeutic effect. Colchicine formulations can be administered to such human or other animals in a conventional dosage form prepared by combining the Colchicine formulations of the present invention with conventional pharmaceutically acceptable carriers or diluents in accordance with known techniques. It will be appreciated by those skilled in the art that the form or nature of the pharmaceutically acceptable carrier or diluent is dependent upon the amount of active material being combined, the route of administration, and other well known parameters.

A "therapeutically effective amount or amount" or "effective amount ", when administered, is an amount sufficient to provide a positive therapeutic response, such as a delay in onset of a clinical condition of the disease or condition, Or amelioration of the disease, as evidenced by a decrease in the severity of the overall clinical symptoms, slow progression of the disease or condition, improvement in the overall health or well-being of the individual, or other parameters well known in the art, Refers to the amount of colchicine formulation.

The present invention also provides the use of a colchicine formulation in the manufacture of a medicament for the treatment of a subject for the treatment of cardiovascular diseases and / or inflammatory disorders, wherein the medicament is administered to one or more other treatment- Is used. "Pre-treated" or "pretreatment" means that an individual has been provided with one or more other treatments prior to taking the medicament comprising the colchicine formulation. Within 2 years, within 18 months, within 1 year, within 6 months, within 2 months, within 6 weeks, 1 year prior to commencing treatment with a medicament containing colchicine formulation Within one month, within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, within 6 days, within 5 days, within 4 days, within 3 days, within 2 days or even within 1 day Lt; / RTI > "Concurrent" or "concomitant" means that an individual takes one or more other therapeutic agents at the same time as taking a medicament comprising a colchicine formulation. The individual is not an individual that responds to prior therapy with prior treatments or therapies, or an individual that is responsive to concurrent treatments or treatments. That is, an individual taking a medicament containing a colchicine formulation may have failed or failed to respond to prior treatment with prior treatment or with prior treatment with one or more prior therapeutic agents consisting of a plurality of therapeutic agents.

All of the foregoing references and all references cited herein are hereby incorporated by reference in their entirety.

While the invention has been illustrated and described in detail in the foregoing description, such illustration and description should be regarded as illustrative or exemplary and not restrictive. It will be understood by those skilled in the art that changes and modifications may be practiced within the scope and spirit of the appended claims. In particular, the present invention encompasses additional implementations that arbitrarily combine the features derived from the various implementations described above and below.

The present invention is further described below with reference to non-limiting exemplary embodiments which provide a more thorough understanding of the present invention and the various advantages thereof. The following embodiments are included to illustrate preferred embodiments of the present invention. Those skilled in the art will appreciate that the techniques referred to in the embodiments referencing the techniques used in the present invention are fully functional in the practice of the present invention and therefore can be considered to constitute preferred modes of practicing the present invention It should be understood. It will be apparent, however, to one skilled in the art, in light of the teachings of this invention, that many similar changes may be made to the specific embodiments mentioned, without departing from the spirit and scope of the invention, .

Example

Example 1: Colchicine sustained-release tablet

This example illustrates a colchicine sustained-release tablet. Tablets use the components and concentrations shown in Table 1 below.

ingredient mg / tablet refine % function Colchin 0.500 0.5 The active pharmaceutical ingredient (API) Lactose monohydrate 59.00 59.0 Filler Pregelatinized starch 7.50 7.5 Filler Hi Prom Melos 6mPa * s 1,000 1.0 Binder Purified Water ¹ q.s. q.s. Diluent and binder for API Lactose monohydrate 10.00 10.00 Filler Retalac (lactose monohydrate and 4000mPa * s 50/50 w / w% hypromellose) 20.00 20.00 Retarder Talc 1.00 1.0 Fluidizing agent Stearic acid 50 1.00 1.0 slush Total weight of tablet [mg]: 100.00 Taken in ^one process

The concentration can be varied to give certain characteristics of the formulation, e. G., A change in the dissolution profile. Table 2 shows the range of each component.

ingredient range function Colchin 0.5-0.75 The active pharmaceutical ingredient (API) Lactose monohydrate 10-80 Filler Pregelatinized starch 5-50 Filler Hi Prom Melos 6mPa * s 1-30 Binder Purified Water ¹ q.s. Diluent and binder for API Lactose monohydrate 10-30 Filler Retalac (lactose monohydrate and 4000 mPa * s 50/50 w / w% of hypromelose)) 5-40 Retarder Talc 0.5-5 Fluidizing agent Stearic acid 50 0.5-5 slush Total weight of tablet [mg]: Taken in ^one process

Example 2: Preparation of colchicine sustained-release tablets

Using the above ingredients, tablets are prepared according to the following instructions:

Granulation: Granulation was performed in a Kenwood mixer. Colchicin and 6mPa * s of high promolos were first weighed and dissolved in purified water, respectively. A 6 mPa * s solution of hiropromelose was placed in a mixer with lactose within 1.5 minutes and mixed for 3 minutes. Thereafter, the colchicine dissolved was sprayed for 15 minutes with continuous mixing of the filler (e.g., lactose monohydrate). These steps were performed at room temperature. The wet granulate was passed through a 1.0 mm hand sieve. Thereafter, it was dried in an oven (Haeraeus) at 45 ° C for 26 hours to have a residual moisture of 0.53%, and passed through a 0.8 mm sieve shaker (Erweka AR 400). Density parameters were examined (Engelmann). Bulk density 0.53 g / ml, Compressed bulk density 0.67 g / ml, Hausner ratio 1.26. Rheology: Flow time 4 seconds; Slope angle 23.8 °.

Blending: After the granulation process, the granulate is compounded with a filler (e.g., lactose monohydrate), a retarding agent (e.g., Retalac) and other excipients (e.g., flow enhancer, fluidizing agent and / or lubricant) Prepare. For this purpose, these ingredients were manually passed through a 0.8 mm sieve and mixed with the granulation for 10 minutes in a cube mixer (Erweka). In one embodiment, the fluidizing agent used may be talc. In other embodiments, the lubricant used may be stearic acid. The granulate is then blended using an appropriate mixer.

Compression of tablets : Compression is needed to make tablets. The mechanical force will define the physical properties of the tablet, particularly the compressive strength of the tablets produced. The mechanical strength interacts with the initial swelling of the tablet and the dilution rate of the tablet core. This action is well known in the art and can be adjusted and controlled during the life cycle of the product.

The tableting was performed with a Korsch (EK 0) tablet press and a round tabletting tool, biconvex, 6 mm in diameter. The average hardness of the tablets was about 100 N +/- 15 N. Tablets weighed about 100 mg in weight were not able to measure the clarity. The fracture strength and hardness were measured with an Erweka Multickeck. Dispersibility was measured using an Erweka Friabilator and Mettler analytical balance. Dimensions were measured with Mitutoyo caliper.

Example 3: Determination of the dissolution profile of a sustained-release colchicine formulation

Dissolution of the colchicine sustained-release formulation was measured at various time points. The composition was dissolved in 500 ml of water at 37 占 폚 and continuously stirred for 6 hours. Samples were taken at various time points to investigate the kinetic of the dissolution process of the drug substance in the hydrophilic matrix system. The colchicine content of the sample was analyzed by HPLC analysis.

Several batches were examined to determine the optimal dissolution profile of the sustained release formulation. The release can be modified by the concentration of hypromellose or by using a different viscous grade of hypromellose (e.g., 1000 mPa or 10000 mPa), or both. In the batches examined below, the viscosity grade remained constant and varied to a concentration of 4000 mPa of the high promolose of the tablet.

Table 3 below summarizes the various compositions tested.

Material name weight [%] Weight / tablet [mg] / Batch [g] -0.5% + 0.5% Stem granules: (common in all three tablet mixes) .PE Colchin 0.500 0.500 7.50 7.46 7.54 Lactose monohydrate EP 59,000 59,000 885.00 880.6 889.4 All pregelatinized starch USP 7.500 7.500 112.50 111.94 113.06 FB Hi Prom Melos 6mPa * s EP / JP / USP 1,000 1,000 15.00 14.93 15.08 Purified water for colchicine * 0.000 4.000 60.00 59.70 60.30 Purified water for Hi Prom Melos * 0.000 8.300 124.50 123.88 125.1 Placement 1: 10% Retalac tablet mix (compression strength = 100 N): Lactose monohydrate EP (filler, 100 mg per tablet) 20,000 20,000 80.0 79.6 80.4 PE Retalac (50% lactose /
50% Hi Prom Melos 4000mPas) 10,000 10,000 40.00 39.8 40.2 Talc EP / JP 1,000 1,000 4.00 3.98 4.02 Stearic acid 50 EP 1,000 1,000 4.00 3.98 4.02 Total weight of tablets: 100,000 100,000 Placement 2: 15% Retalac tablet mix (compression strength = 100 N): Lactose monohydrate EP (added 100mg per filler tablet) 15,000 15,000 60.00 59.7 60.3 PE Retalac (50% lactose /
50% Hi Prom Melos 4000mPas) 15,000 15,000 60.00 59.7 60.3 Talc EP / JP 1,000 1,000 4.00 3.98 4.02 Stearic acid 50 EP 1,000 1,000 4.00 3.98 4.02 Total weight of tablets: 100,000 100,000 Placement 3: 20% Retalac tablet mix (compressive strength = 100 N): Lactose monohydrate EP (added 100mg per filler tablet) 10,000 10,000 40.00 79.6 80.4 PE Retalac (50% lactose /
50% Hi Prom Melos 4000mPas) 20,000 20,000 80.00 79.6 80.4 Talc EP / JP 1,000 1,000 4.00 3.98 4.02 Stearic acid 50 EP 1,000 1,000 4.00 3.98 4.02 Total weight of tablets: 100,000 100,000 Placement 4: 30% Retalac tablet mix (compressive strength = 50 N and 130 N): Lactose monohydrate EP (added 100mg per filler tablet) 0.000 0.000 00.00 0.0 0.0 PE Retalac (50% lactose /
50% Hi Prom Melos 4000mPas) 30,000 30,000 120.00 119.40 120.60 Talc EP / JP 1,000 1,000 4.00 3.98 4.02 Stearic acid 50 EP 1,000 1,000 4.00 3.98 4.02 Total weight of tablets: 100,000 100,000 Placement 5: 0% Retalac tablet mix (compressive strength = 100 N): Lactose monohydrate EP (added 100mg per filler tablet) 30,000 30,000 120.00 119.40 120.60 PE Retalac (50% lactose /
50% Hi Prom Melos 4000mPas) 0.000 00.000 00.00 0.0 0.0 Talc EP / JP 1,000 1,000 4.00 3.98 4.02 Stearic acid 50 EP 1,000 1,000 4.00 3.98 4.02 Total weight of tablets: 100,000 100,000

The dissolution profiles of the various batches are presented in Tables 4-6 and 1-4. In particular, the dissolution profiles of batches 1-3 are summarized in Table 4 and FIG. In the profile of batch 1, approximately 92% is released within about 30 minutes, and then released constantly. Complete dissolution occurred after 2 hours. Batch 2 is released about 83% within about 30 minutes, and then released constantly. Complete dissolution occurred after 2 hours. Batch 3 is released about 74% within about 30 minutes, and then released constantly. Complete dissolution occurred after 2 hours.

Table 4 time time time time time Concentration of retarding agent Sample 0 0.5 One 2 4 10% Retalac One. 90.6 98.1 99.1 98.9 2. 93.7 97.6 97.5 97.6 3. 98.6 99.3 99.5 99.8 4. 93.7 97.5 98.1 98.2 5. 89.9 93.7 93.7 93.8 6. 89.6 97.2 97.5 97.6 Average 0 92.7 97.2 97.6 97.7 15% Retalac One. 75.1 89.2 95.9 96.0 2. 74.5 91.3 95.0 94.9 3. 85.7 99.1 100.3 100.2 4. 86.9 98.2 100.1 99.3 5. 84.7 93.9 94.6 94.3 6. 90.7 96.0 95.7 96.1 Average 0 82.9 94.6 96.9 96.8 20% Retalac One. 68.1 87.7 97.8 97.8 2. 62.0 83.2 95.2 96.3 3. 85.4 95.2 98.2 98.3 4. 76.6 94.7 97.2 96.9 5. 71.8 94.5 103.5 103.1 6. 80.6 95.4 99.0 98.9 Average 0 74.1 91.8 98.5 98.6

The dissolution profile of batch 4 is summarized in Table 5 and FIG. Batch 4A is released about 30% within about 30 minutes, and then released constantly. Complete dissolution occurred after 6 hours. Batch 4B is released about 23% within about 30 minutes, and then released constantly. Complete dissolution occurred within 6 hours. In this embodiment, the hardness difference of the tablet causes a difference in the emissivity. Figure 3 shows the dissolution profile of batches 1-4.

Table 5 time time time time time Retardant concentration Sample 0.5 One 2 4 6 (A)
30% Retalac
50N hardness No.1 30.5 47.1 70.7 96.5 96.9 No.2 34.5 49.3 70.6 95 98 No.3 27.8 42.6 64.6 90.9 95.8 30.9 46.3 68.6 94.1 96.9 (B)
30% Retalac
130N Hardness No.4 22.5 37.1 54.9 81.2 92.5 No.5 25.9 42 67.1 94.5 108.7 No.6 23.3 36.5 57.8 87.9 101.8 23.9 38.5 59.9 87.9 101.0

The dissolution profile of batch 5 is summarized in Table 6 and FIG. Batch 6 is an immediate release version of the composition. The profile of batch 5 shows 90% release within 5 minutes. Complete dissolution occurred within 2 hours.

Table 6 minute minute minute minute minute minute minute Retardant concentration Sample 0 5 15 30 45 60 120 0% Retalac One. 92.2 96.8 96.8 96.9 97.2 2. 96.7 100.6 99.9 100.3 100.7 3. 94.7 100.8 100.5 100.9 101.1 4. 86.5 92.7 92.9 93.1 93.3 5. 85.6 91 91.7 91.4 91.8 6. 84.5 88.1 87.1 87.1 87.5 Average 0 90.0 95.0 94.8 95.0 95.0 100

As described above, the release profile of the sustained release composition can be changed to a specific or desired target release by adjusting the amount of retardant (i.e., Retalac) as well as the hardness of the tablet. Release is determined by various factors such as corrosion of the outer layer of colchicine (i.e., immediate release portion) and diffusion of the colchicine inner layer (i.e., sustained release portion). Since the percentage of colchicine is low in the sustained release formulation and the tablet is small, this balance between corrosion and diffusion is very sensitive and must be finely tuned to reach a very specific dissolution profile.

Example 4: Determination of dissolution profile in ethanol of a sustained release colchicine formulation

In order to assess the drug dumping or the ability of the composition to dissolve alcohol, dissolution in ethanol of the colchicine sustained release formulation was measured at various time points. The composition was dissolved in three solutions, namely 500 ml of 5%, 20% and 40% ethanol at 37 占 폚 and stirring was continued for 6 hours. Samples were taken at different times to investigate the dissolution process kinetic of the drug substance within the hydrophilic matrix system. The colchicine content in the sample was analyzed using HPLC analysis.

Example 5: Therapeutic effect of sustained-release colchicine formulation

The therapeutic efficacy of the colchicine sustained-release formulation was evaluated in a multi-dose, randomized, cross-over clinical trial, and about three 0.5 mg colchicine sustained-release formulations (e.g., test products 1, 2 and 3) (Control) are administered to healthy volunteers to assess their bioavailability. The primary goal of the experiment is to assess the pharmacokinetics (PK) of the test and control drugs in the blood and in neutrophils or leukocytes.

Objective: The primary objective of the present study was to compare the pharmacokinetics of colchicine to test products versus control products in healthy human volunteers. In particular, colchicine levels in blood (referred to herein as blood PK), neutrophils or leukocytes (referred to herein as neutrophil PK) are analyzed during control and test product treatment.

The test hypothesis is that if colchicine is administered in the same amount as a sustained-release tablet, it maintains the absolute bioavailability (area under the curve, AUC) of the equivalent peak as the peak level (Cmax) decreases. Since neutrophils, which account for 60-70% of leukocytes, are generally recognized as playing a central role in inflammatory responses and colchicine is considered to play an important role in some diseases used as therapeutic agents, neutrophil colchicine concentration . Therefore, leukocytes or neutrophils can be analyzed for the purpose of this experiment. Thus, the term neutrophil as used herein also refers to leukocytes when used. Since colchicine is preferentially accumulated in neutrophils and is known to inhibit a number of its pro-inflammatory functions, it is considered the main target of colchicine therapy. Thus, there is particular interest in identifying whether colchicine reaches similar concentrations in isolated neutrophils or leukocytes, which will provide information on potential bioequivalence. Therefore, blood will be drawn at various times during the course of the experiment to check for colchicine concentrations in the blood and neutrophils.

General experiment design: This experiment is designed as a random, crossed experiment. This would consist of three groups of patients (n = 3 x at least 8). Group 1 will be provided with a control or test drug for about 8-14 days. After the washout period, Test Drug 1 will be provided for approximately 8-14 days. Group 2 will receive the control drug for the same time. After the pause, test drug 2 will be provided for the same amount of time. Group 3 will receive the control drug for the same time. After a pause, test drug 3 will be provided for the same amount of time. Participants in this study were treated for the first 24 hours for inpatients and for the rest of the outpatients. A sufficiently long rest period exists between the two experiments.

Object participation: The patient will consist of 3 groups (n = 3 x at least 8). For each test drug, healthy volunteers are randomly grouped into one drug in the first round. After a sufficient rest period, the same individuals are given a control drug.

Experimental period: The test drug is administered once per day for a continuous day of about 8-14 days. The experiment consists of 24 h blood PK (high frequency data collection). Neutropenia PK is analyzed at the end of the experiment at the interval between which colchicine levels can be reliably measured.

Therapeutic Uses: Examples of therapeutic uses are shown below.

Cycle 1 Dormant Cycle 2 Group 1 14 days
Control or Test 1 14 days
14 days
Test 1 or control group Group 2 14 days
Control or Test 2 14 days
14 days
Test 2 or control group Group 3 14 days
Control or Test 3 14 days
14 days
Test 3 or control group

Research techniques and data analysis: Chemically analytical techniques (HPLC) or immunological techniques (radioimmunoassays) can be used to evaluate colchicine and, optionally, its metabolites. The collected data is analyzed using appropriate data management and analysis software.

Population group: The population of the experiment is composed of healthy male volunteers. The inclusion criteria for the study should be 25-40 years of age for the patient; There are no major competing convictions or contraindications to colchicine treatment; I agree with the experiment and intend to favor random assignment. Patients who meet the following criteria are excluded: treatment with other anti-inflammatory / immunosuppressant drugs is in progress; Medicament interaction with colchicine; treatment with known drugs; Kidney / liver injury; Known hypersensitivity to colchicine.

Treatment plan: Drugs are provided once a day in the morning.

Data Collection Plans: In the case of blood PK, blood is drawn at short intervals (24 hours) in the beginning of the experiment (sufficient time to establish pharmacokinetic data, eg: -1, + 0.5h, 1h, 1.5h, 2h, 3h , 4h, 5h, 7h, 10h, 12h, 15h and 24h (before the next application). Additional time zones may be 24h and 72h after drug withdrawal at the end of the experiment to assess the drug's resting period. PK analysis includes colchicine blood levels. Techniques suitable for blood separation and colchicine quantification apply.

In the case of neutrophil PK, neutrophils are separated or purified from blood stocks drawn at various times. Neutrophils are collected at least once at the beginning of the experiment and at the end of the experiment. PK analysis included colchicine concentrations in isolated neutrophils.

Example 6: Therapeutic effect of a quasi-drug formulation in a cardiovascular disease patient

A prospective, randomized observer-blinded end-point experiment was performed to assess the therapeutic effect of a quadriceptive formulation in a cardiovascular patient, so that addition of 0.5 mg / day of colchicine to standard secondary prevention regimens, including aspirin and high-dose statins, And to reduce the risk of cardiovascular disease in patients with diagnosed and clinically stable coronary artery disease. This experiment is described in PCT / AU2013 / 001261, the entire contents of which are incorporated herein by reference.

Experimental Design and Design: The LoDoCo experiment was conducted under the auspices of the Heart Research Society of Western Australia. It was designed by a top researcher enrolled in the Australian Clinical Trials Register (12610000293066) and was ethically approved in July 2008 by the Human Research Ethics Committee at Sir Charles Gairdner Hospital in Perth, Western Australia. There was no external funding.

The experiment is a prospective random, open, blind, end-point design. Consensus eligible patients with established coronary artery disease visited for routine clinical evaluation were randomly assigned to a 0.5 mg / day colchicine group and a non-colchicine group, without any other changes in the patient's medical treatment. All outcomes were assessed by an experienced judge who did not know the treatment group.

Scale and Eligibility of the Experiment: A plan to recruit an experimental group, including 250 patients who were allowed colchicine for at least 4 weeks from the random assignment, 28 randomly assigned controls and 250 randomly assigned controls Respectively. Patients were eligible to participate in the study if they met each of the following criteria: 1) identified as coronary artery disease on angiography; 2) age 35-85 years; 3) clinically stable for at least 6 months, 4) not a significant competitive co-relaxation or use restriction for colchicine treatment, 5) follow-up care and routine follow- And 6) in favor of consent and randomization in the experiment. Patients with bypass surgery were enrolled only if they had undergone bypass surgery for more than 10 years, or if there was evidence of graft failure by angiography or if the stent was performed after bypass surgery. Prior consent was obtained from all patients prior to random assignment.

Random assignment: A random sequence was created by a computer, always kept secret to the investigator, and managed by a research assistant who did not participate in the evaluation or management of the experimental patient. When an assistant received the consent, he entered the patient's demographic data into the database and advised the investigator and patient to implement the patient-assigned treatment group. Despite being selected to use the lowest available dose of colchicin available, many patients were expected to miss early randomized therapy due to gastrointestinal side effects. To ensure that the necessary personnel in the treatment group are able to perform the actual treatment, the protocol allows the research assistant to assign the newly recruited patient to the treatment group if the patient has stopped Colchicine due to side effects in the first month. Patients who did not survive the treatment were also left in the experiment, followed up in the usual way, and included in the intention to treat analysis.

Intervention: For randomly assigned patients with active therapy, the patient's recommended cardiologist prescribed 0.5 mg colchicine daily. The drug was distributed by a general pharmacist and, if necessary, reimbursed the patient for these scripts. All other treatments continued as normal.

Follow-up and clinical outcomes: Patient compliance and performance data were collected at regular follow-up visits and at unplanned hospital admissions. Acute coronary syndrome (ACS) is associated with acute myocardial infarction (AMI) or serum troponin elevation, which is characterized by acute ischemic chest pain above serum normal troponin level (a) (B) Unstable Angina Brainwald classification types (IB and IIB), which are proven by recent worsening of angina in patients with changes in angiography. ACS described the characteristics as being stent-related in the presence of significant phosphorus-stent stenosis or acute stent thrombotic evidence. A hospital out-of-hospital outage was defined as a non-fatal hospital out-of-hospital out-of-pocket condition defined as a sudden death or documented contraction confirmed in the patient's death certificate, recovery from sudden changes due to ventricular tachycardia or ventricular fibrillation. A non-cardiac ischemic stroke was defined as an ischemic stroke identified by CT or MRI as judged by a treatment neurologist because it is not due to atrial fibrillation or intracerebral hemorrhage.

Primary efficacy outcomes were composite, ACS, fatal or non-fatal hospital out-of-hospital or non-cardiac ischemic stroke. Secondary outcomes were (a) individual components of primary outcome, and (b) ACS factors independent of stent disease.

Timeline: The pre-determined duration of the trial was at least two years of follow-up for all patients. The experiment ended on May 31, 2012. In May, we telephoned all survivors and collected compliance and performance data on the last day of follow-up. Final performance data were available in all patients, and no patients were followed up.

Statistical Verification Assumptions: Assuming the combined incidence (ACS, out-of-hospital or non-cardiac ischemic stroke) of the control group to be 8%, the accrual interval is 2 years and the follow- Provides a> 80% verifiability and the risk rate is <0.50 based on 5% significance level on both sides.

Data analysis: Summary statistics, including mean and standard deviation, calculated all baseline characteristics by treatment group. Time to event outcomes are all randomly assigned, (1) date of occurrence or death; Or (2) days from the end of the experiment in patients who did not experience a given event. As determined in advance, primary efficacy analysis was based on the intent to treat. Therapeutic intent analysis included all randomly assigned entities and all occurrences from the randomly assigned day to the end of the experiment. The end of the experiment was fixed on May 31, 2012. A pre-determined on-treatment analysis was also performed on the basis of patients who were tolerated and followed for treatment at the first month of randomization. Included in this analysis are all events that occurred from the date of random assignment to the time of failure to comply with colchicine treatment.

For all results, the time-to-first-event is written in a CAPLAN-MAYER plot. Primary efficacy outcomes were analyzed using the Cox proportional hazards model, which included a control group or treatment group coded with colchicine. Secondary outcomes were analyzed similarly. In addition, the first-line analysis included the use of atorvastatin 40 mg or higher (atorvastatin 40 mg or higher), or a combination therapy with atorvastatin, clopidogrel, or both, by gender, age, diabetes diagnosis, past myocardial infarction, unstable angina pectoris, coronary artery bypass surgery, coronary angioplasty, ), Beta-blockers, calcium blockers and ACE inhibitors.

RESULTS: From August 2008 to April 2010, 901 patients with stable coronary artery disease visited for routine outpatient cardiac screening were evaluated for eligibility. Of these, 297 (33%) did not meet the overall criteria, 72 (8%) refused to participate, and 532 (59%) were enrolled in the study, 250 of whom were control subjects and 282 were randomized Respectively. Of the randomly assigned patients, 32 (11%) reported initial hypersensitivity due to gastrointestinal side effects, and 7 patients reported no treatment initiation. A total of 532 randomized patients were followed up for at least 24 months and up to 44 months during the study period. The mean follow - up period was 36 months.

Outcome: The primary outcome was in 55/532 patients, including 15/282 (5.3%) patients assigned to the colchicine treatment group and 40/250 (16%) patients assigned to the control group [risk ratio 0.33 , 95% CI; 0.18-0.59; p <0.001, required for treatment group 11). Sensitivity analysis was performed on the primary outcome and adjusted for the use of calcium channel blockers and beta blockers. These results were consistent with the first analysis.

The effect of colchicine on primary outcome was clear at the beginning, and the effect of colchicine continued throughout the tracing period. There was no evidence of differential treatment effects due to any clinical or therapeutic variables.

The decrease in primary outcome was mainly due to a decrease in the number of ACS patients (13/282 (4.6%) vs. 34/250 (13.4%), with a risk of 0.33; 95% CI; 0.18-0.63; p <0.001). Hospital out - of - hospital and non - cardiac ischemic strokes were rare, but decreased in the treatment group.

Of the 47 patients with ACS, eight patients (17%) had stents (two in each group showed evidence of acute stent thrombosis and two in each group showed evidence of severe stent stenosis). In addition, through analysis, patients randomly assigned to treatment group had a stent disease-related ACS (9/282 (3.2%) vs. 30/250 (12%) hazard rate of 0.26, 95% CI; 0.12-0.55; p <0.001) , Or AMI (4/282 (1.4%) vs. 14/250 (5.6%) hazard ratio 0.25, 95% CI; 0.08-0.76; p = 0.014) or UA (5/282 (6.4%), the risk of 0.27, 95% CI; 0.10-0.75; p = 0.011).

(N = 1) and UA (n = 3) in 4 (10%) of these patients did not receive therapy after the first month due to the initial unacceptable or non- ) Caused ACS. Patients who adhered to therapy after the first month of randomization and who were allowed to receive therapy had significantly fewer pathological cases than controls (11/243 (4.5%) vs. 40/250 (16%) with a risk of 0.29, 95% CI ; 0.15-0.56; p < 0.001). The results of all treatments were consistent with the results of intent to treat.

In the control group, 10 patients died, whereas the colchicine group died in 4 patients. Of these 10 control subjects, 5 were considered cardiac deaths; Two patients died after cardiac arrest, two patients had cardiac stroke after myocardial infarction, and one died after bypass surgery. Four patients in the colchicine group died of noncardiac causes.

This study demonstrated that the addition of colchicine at 0.5 mg / day to standard therapy for patients with stable coronary artery disease significantly reduced the risk of cardiovascular events such as ACS, cardiac arrest and noncardiac ischemic stroke It does. The availability of colchicines was achieved in a wide use background in effective secondary prevention strategies such as high dose statins, as evidenced by low incidence in the control group. The colchicine additive effect was evident at the beginning, persisted over time, and was primarily caused by a reduction in STD-associated ACS disease.

Example 7: Capacity titration of sustained release colchicine formulations

To determine the appropriate dosage, a sustained release formulation may be administered to a group of patients having different weights. Assume that a 0.5 mg tablet provides a constant plasma colchicine level in patients with an average body weight and that this specific level should be reached in order to achieve efficacy in all patients. A PK analysis of 0.5 mg congestion is performed on various weight groups . In high-weight patients, blood levels (Cmax and AUC) are low and dose adjustment is expected to be needed to increase the dose.

Objective: The primary objective of this study was to compare the pharmacokinetics of 0.5 mg colchicine tablets in healthy human volunteers in at least two different weight groups. In particular, blood colchicine levels are analyzed at the time of treatment. The investigated hypothesis is that the administration of the same amount of colchicine indicates different levels of colchicine depending on body weight. Body weight and colchicine levels were inversely correlated.

Overall experimental design: This experiment is designed as a random, cross-over experiment. n = At least 8 people are selected according to body weight. When two groups are made, 50% will be underweight (eg <65 kg) and 50% will be solid (eg> 90 kg).

Experiment period: The test drug should be administered once. The experiment consists of 24 h blood PK (high frequency data collection).

Research techniques and data analysis: Chemical analysis techniques (HPLC) or immunological techniques (radioimmunoassay) can be used to evaluate colchicine. The collected data is analyzed using appropriate data management and analysis software.

Population group: The population of the experiment is composed of healthy male volunteers. The inclusion criteria for the study should be 25-40 years of age for the patient; Weight is between 50 kg and 120 kg; Healthy; There are no major competing convictions or contraindications to colchicine treatment; I agree with the experiment and are willing to be randomly assigned. Patients who meet the following criteria are excluded: treatment with other anti-inflammatory / immunosuppressant drugs is in progress; Medicament interaction with colchicine; treatment with known drugs; Kidney / liver injury; Known hypersensitivity to colchicine.

Treatment plan: Drugs are provided once every morning on the day of the experiment.

Data Collection Plans: In the case of blood PK, blood is drawn at short intervals for 24 hours at the start of the experiment (sufficient time to establish pharmacokinetic data, eg: -1, + 0.5h, 1h, 1.5h, 2h, 3h , 4h, 5h, 7h, 10h, 12h, 15h and 24h (before the next application). Additional time zones may be 24h and 72h after drug withdrawal at the end of the experiment to assess the drug's resting period.

Example 8: Non-clinical pharmacokinetic studies of the sustained-release (SR) versus quadriceps (IR) colchicine

In this experiment, a sufficient number of suitable experimental animals were used (eg rodents such as mice or rats, at least 5 animals per group). The control drug is an IR tablet of colchicine. The test drug is SR purified from colchicine.

Control mice were treated with a therapeutic window (range of colchicine concentrations in plasma where therapeutic effects could be observed, which were determined to be low enough for the LD50 and at least 6 times lower than the maximal level, Lt; / RTI &gt; and, optionally, set) as the first dose of IR colchicine. In the test group, SR colchicine of the same dose is given in the first dose. Blood is drawn from both groups at 0.25h, 0.5h, 0.75h, 1h, every hour for the next 12 hours, and every 3 hours for up to 24 hours. At the same time, take streaks in test animals and control animals cages after 3h, 6h, 12h and 24h (test animals and control animals should not be placed in the same case).

Primary readout: colchicine plasma level. Secondary information: Measure colchicine and its metabolites on the sides to see if recurrent long-term recycling occurs at low levels in test animals compared to control animals. Blood samples are processed and colchicine levels in plasma are determined by HPLC analysis or equivalent quantitative methods.

RESULTS: In this experiment, the total absorption of colchicine (area under the curve) is expected to be similar in both test and control animals. However, in the control animals, the colchicine uptake reaches a peak at about 1 hour after administration, and then decreases rapidly. After 2-3 hours, colchicine levels are below the therapeutic range. Also, due to the long-term recycle of non-metabolized colchicine, re-absorption occurs, which appears as a characteristic secondary peak after 3-6 hours.

However, in the case of test animals (SR), colchicine levels will rise more slowly, but not colchicine peak levels observed in control animals. Peak levels are observed after 3-8 hours and then gradually decrease. Therapeutic colchicine levels are maintained for at least 12 hours. Since colchicine is more fully metabolized in the liver, long-term recycling is achieved at low levels and secondary peaks are not observable. As secondary information, the sides of the test and control animals are examined to ensure that the long-term recycle is at a low level in the test animal as compared to the control animal. It can be seen that the proportion of unmodified colchicine versus metabolized colchicine is higher in control animals than in test animals. In other words, SR colchicine implements more complete colchicine metabolism in the liver.

Example 9: Non-clinical safety testing of colchicine vs. SR vs. IR

In this experiment, a sufficient number of suitable experimental animals were used (eg rodents such as mice or rats, at least 5 animals per group). The control drug is an IR tablet of colchicine. The test drug is SR purified from colchicine.

In the control mice, the therapeutic range (range of colchicine concentrations in plasma where therapeutic effects can be observed, which is determined by the laboratory animal species used as the minimum level which is sufficiently low at LD50 and about 6 times lower than the maximum level, Lt; / RTI &gt; dose of IR &lt; RTI ID = 0.0 &gt; colchicine &lt; / RTI &gt; In the test group, SR colchicine of the same dose is given in a single dose / day. As another example, the test animals and the control animals are provided with a total of 2 days a day, once in the morning and once in the evening. The experimental period is two weeks.

Primary information is gastrointestinal side effects (eg, convulsions, diarrhea, etc.). This is evaluated in three ways. Each day, the behavior of the test animals is observed in a predetermined standardized way of assessing the signal of the disease. Second, investigate the presence of morphologic and apoptotic epithelial cells on a daily basis. Third, each animal is sacrificed at predetermined time points and the histopathological signals for colchicine toxicity in the small intestine and colon are examined.

Results: During the experimental period, it can be expected that the control animals have more gastrointestinal side effects than the test animals. Thus, SR colchicine exhibits a better safety profile than IR colchicine.

Example 10: Clinical safety test of colchicine vs. SR vs. IR

If the animal is judged to be inappropriate for side effects associated with colchicine administration, equivalent experiments are performed in humans. It is performed in healthy adult volunteers or in patients requiring additional colchicine. Use enough personnel to obtain statistical significance. Test and control drugs consist of a colchicine SR or IR oral solid dosage form with a dose of 0.25 - 1 mg. To reach the therapeutic level of colchicine, a significant high dose is administered. As a different example from once daily dosing, the test drug is given twice daily as mentioned in Example 3 above. As another example, to control placebo effects, include placebo groups in both experimental settings. The duration of the experiment is 2 weeks to 1 month.

Those skilled in the art to which the invention pertains will anticipate many variations and other implementations of the invention described herein that have the benefit of the teachings of the foregoing description and the accompanying drawings. It is, therefore, to be understood that the invention is not to be limited to the specific embodiments described, and that modifications and other embodiments are within the scope of the embodiments described herein and the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims (63)

(a) colchicine or a pharmaceutically acceptable salt thereof;
(b) a retarding agent; And
(c) at least one pharmaceutically acceptable excipient.
A sustained release formulation of colchicine as an active ingredient. The formulation of claim 1, wherein said formulation releases colchicine in an amount of about 80% or more within 24 hours, within 16 hours, within 12 hours, within 8 hours, within 6 hours, within 4 hours, within 3.5 hours, or within 1.5 hours in vitro , Formulation. 4. The formulation of claim 1 or 2, wherein the formulation releases colchicine at least about 20% within the first 30 minutes in vitro. 4. The formulation according to any one of claims 1 to 3, wherein the retarder is selected from the group consisting of cellulose ethers, cellulose esters, acrylic acid copolymers, waxes, gums, glyceryl fatty acid esters and sucrose fatty acid esters. . 5. The formulation according to any one of claims 1 to 4, wherein the delaying agent comprises hypromellose. 6. The formulation of any one of claims 1 to 5, wherein the retarder is included in the formulation in an amount from about 5 wt% to about 40 wt%. 7. A formulation according to any one of claims 1 to 6, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a binder, a filling agent, a glidant and a lubricant or a combination thereof. 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutically acceptable excipient is a binder selected from the group consisting of starch, gelatin, polyvinylpyrrolidone, cellulose derivatives, polyvinyl alcohol, Formulation. 9. The formulation according to any one of claims 1 to 8, wherein the cellulose derivative is selected from the group consisting of hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC). 10. The formulation according to any one of claims 1 to 9, wherein the cellulose derivative forms a hydrophilic matrix. 11. A pharmaceutical composition according to any one of claims 1 to 10 wherein the pharmaceutically acceptable excipient is selected from the group consisting of sucrose, lactose, especially lactose monohydrate, trehalose, maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone, Selected from the group consisting of sodium alginate, methacrylic acid DVB, crosslinked PVP, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch and combinations thereof &Lt; / RTI &gt; 12. Formulation according to any one of claims 1 to 11, wherein the total content of the filler in the formulation is from about 5.0 wt% to 90.0 wt of the formulation. 13. A formulation as claimed in any one of claims 1 to 12 wherein the pharmaceutically acceptable excipient is a fluidising agent selected from the group consisting of colloidal silicon dioxide, magnesium trisilicate, cellulose powder, talc and tribasic calcium phosphate. 14. The formulation according to any one of claims 1 to 13, wherein the total content of the fluidizing agent in the formulation is from about 0.5 wt% to about 5 wt% of the formulation. 15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the pharmaceutically acceptable excipient is selected from the group consisting of glyceryl behenate, stearic acid, vegetable hydrogenated oil, stearyl alcohol, leucine, polyethylene glycol, magnesium stearate, glyceryl monostearate Wherein the lubricant is selected from the group consisting of polyethylene glycol, ethylene oxide polymer, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine and colloidal silica. 16. Formulation according to any one of claims 1 to 15, wherein the lubricant is included in an amount of about 0.5 wt% to about 5 wt% of the formulation. 17. A composition according to any one of claims 1 to 16 wherein the formulation is selected from the group consisting of tablets, pills, capsules, caplets, suppositories, skin patches, creams, sublingual formulations, eye drops, gels, ointments, troche, , A pouch, a sprinkle, or a combination of a surgically insertable medical device. 18. The formulation of any one of claims 1 to 17, wherein the dosage form is tablet. 19. A formulation according to any one of claims 1 to 18, wherein the tablet has a compression strength of from about 30 N to about 130N. 20. The dosage form according to any one of claims 1 to 19, wherein the total amount of colchicine in the formulation is from about 0.1 to about 5.0 mg / 21. The method according to any one of claims 1 to 20, wherein the amount of colchicine per dose is from 0.1 mg to 2.0 mg, from 0.1 mg to 1.75 mg, from 0.1 mg to 1.5 mg, from 0.1 mg to 1.25 mg, from 0.1 mg to 1.0 mg , 0.1 mg to 0.75 mg, 0.1 mg to 0.6 mg, 0.1 mg to 0.5 mg or 0.25 mg to less than 0.5 mg. 22. The formulation of any one of claims 1 to 21, wherein the total amount of colchicine in the formulation is from about 0.25 wt% to about 0.75 wt% of the formulation. 22. A formulation according to any one of claims 1 to 22 for use in the prevention and / or treatment of cardiovascular diseases. 24. The method according to any one of claims 1 to 23, wherein said cardiovascular disease is selected from the group consisting of acute pericarditis, recurrent pericarditis, pericardiotomy syndrome (PPS) and cardiovascular disease in patients with stable coronary artery disease The formulations are selected. 25. The use of any one of claims 1 to 24 for the manufacture of a medicament for use in combination with conventional therapy for prolonged prevention of acute cardiovascular disease in a patient having established stable coronary disease, 26. The formulation of any one of claims 1 to 25 wherein the acute cardiovascular condition is acute coronary syndrome, an out-of-hospital cardiac arrest, or a noncardioembolic ischemic stroke. 27. A formulation according to any one of claims 1 to 26, wherein said conventional treatment comprises administration of a colchicine-compatible statin. 28. A formulation according to any one of claims 1 to 27, wherein the colchicine-incompatible statin is administered in fixed combination or unfixed combination with colchicine, 29. A pharmaceutical composition according to any one of claims 1 to 28, wherein the colchicine-incompatible statin is atorvastatin, rosuvastatin, simvastatin, pravastatin, derivatives or salts thereof &Lt; / RTI &gt; 22. A formulation according to any one of claims 1 to 22 for use in the prophylaxis and / or treatment of inflammatory diseases. 31. A formulation according to any one of claims 1 to 22 or 30 wherein the inflammatory disease is selected from the group consisting of gout, familial Mediterranean fever, Behcet's disease, aging macular degeneration and Alzheimer's disease. 31. The formulation of any one of claims 1 to 22, 30 or 31, wherein the total daily dose of colchicine administered to the subject is about 0.75 mg or less. 22. A method for the treatment of colchicine comprising administering to a subject a therapeutically effective amount of a sustained release formulation of Colchicin according to any one of claims 1 to 22.
A method for the treatment and / or prevention of cardiovascular diseases. 34. The method of claim 33, wherein said cardiovascular disease is selected from the group consisting of acute pericarditis, recurrent pericarditis, post-pericardial syndrome (PPS) and cardiovascular disease in patients with stable coronary artery disease. 35. The method of claim 33 or 34, wherein the total amount of colchicine in the formulation is from about 0.1 to about 5.0 mg / dose. 35. The method of any one of claims 33 to 35, wherein the amount of colchicine per dose is from 0.1 mg to 2.0 mg, from 0.1 mg to 1.75 mg, from 0.1 mg to 1.5 mg, from 0.1 mg to 1.25 mg, from 0.1 mg to 1.0 mg , 0.1 mg to 0.75 mg, 0.1 mg to 0.6 mg, 0.1 mg to 0.5 mg or 0.25 mg to less than 0.5 mg. 37. The method according to any one of claims 33 to 36, wherein the total daily amount of colchicine administered to said subject is no more than about 0.75 mg. 37. The method of any one of claims 33 to 37, further comprising administering to the subject a conventional treatment for prolonged prevention of acute cardiovascular disease in a patient with established stable coronary artery disease. 39. The method of any one of claims 33-38, wherein the acute cardiovascular condition is an acute coronary syndrome, an out-of-hospital cardiac arrest, or a non-cardiac ischemic stroke. 40. The method according to any one of claims 33 to 39, wherein said conventional treatment comprises administering a colchicine-incompatible statin. 40. The method according to any one of claims 33 to 40, wherein the colchicine-incompatible statin is atorvastatin, rosuvastatin, simvastatin, pravastatin, derivatives or salts thereof &Lt; / RTI &gt; 22. A method for the treatment of colchicine comprising administering to a subject a therapeutically effective amount of a sustained release formulation of Colchicin according to any one of claims 1 to 22.
A method for the treatment and / or prevention of inflammatory diseases. 43. The method of claim 42, wherein said inflammatory disease is selected from the group consisting of gout, familial Mediterranean fever, Behcet's disease, aging macular degeneration and Alzheimer's disease. 44. The method of claim 42 or 43 wherein the total amount of colchicine in the formulation is from about 0.1 to about 5.0 mg / dose. 45. The method of any one of claims 42 to 44, wherein the amount of colchicine per dose is from 0.1 mg to 2.0 mg, from 0.1 mg to 1.75 mg, from 0.1 mg to 1.5 mg, from 0.1 mg to 1.25 mg, from 0.1 mg to 1.0 mg , 0.1 mg to 0.75 mg, 0.1 mg to 0.6 mg, 0.1 mg to 0.5 mg or 0.25 mg to less than 0.5 mg. 45. The method according to any one of claims 42 to 45, wherein the total daily amount of colchicine administered to said subject is no more than about 0.75 mg. (A) - (E).
(A) dissolving colchicine in an acceptable solvent, water, such that the colchicine is from about 0.25 to about 0.75% by weight of the total composition;
(B) adding a binder and a filler to the step A to produce a wet granule;
(C) drying the wet granulate of step B;
(D) blending the dried granulate of step C with a retarder, a filler, a fluidizing agent and a lubricant; And
(E) compressing the final granulate obtained in step D to produce tablets. 49. The method of claim 47,
In step A, the binder is a hypromellose;
In step B, the filler used is lactose monohydrate and pregelatinized starch;
In step D, the retarding agent used is Retalac; Wherein the filler used is lactose monohydrate, the fluidizing agent used is talc, and the lubricant used is stearic acid. 48. A method according to claim 47 or 48, wherein the specific ingredients and the ingredients used are as follows:
ingredient mg / tablet refine %
Colchin 0.500 0.5
Lactose monohydrate 59.00 59.0
Pregelatinized starch 7.50 7.5
Hi Prom Melos 6mPa * s 1,000 1.0
Purified water^One q.s. q.s.
Retalac (lactose monohydrate and 4000mPa * s of Hi Prom Melos)
Compound 50/50 w / w%) 5.0 - 40.00 5.0 - 40.0
Talc 1.00 1.0
Stearic acid 50 1.00 1.0
Total weight of congestion [mg]: 100.00 A shaped and compressed sustained release therapeutic composition comprising a colchicine combined with a matrix and an excipient,
Wherein the excipient comprises a hypromellose,
Wherein the total amount of said excipient is effective to bind said colchicine in a sustained release solid matrix and is at least about 99% by weight of said shaped and compacted composition. 50. The method of claim 50, wherein said composition comprises at least about 80% of said colchicine in a test tube within 24 hours, within 16 hours, within 12 hours, within 8 hours, within 6 hours, within 4 hours, within 3.5 hours, Of the sustained-release therapeutic composition. 52. The composition of claim 50 or 51, wherein the composition releases at least about 20% of the colchicine within the first 30 minutes in vitro. A shaped and compressed colchicine sustained-release tablet made by wet granulating colchicine with an excipient in an amount sufficient to be from about 0.25 to about 0.75 weight percent of the total composition,
The excipient comprises a colchicine sustained-release tablet comprising:
ingredient % range
Lactose monohydrate 10-80
Pregelatinized starch 5-50
Hi Prom Melos 6mPa * s 1-30
Purified water^One q.s.
Retalac (lactose monohydrate and 4000mPa * s of Hi Prom Melos)
Compound 50/50 w / w%) 5-40
Talc 0.5-5
Stearic acid 50 0.5-5 55. The tablet of claim 53, wherein the total amount of excipient is at least about 99% of the total amount of the shaped and compacted composition. A method of treating a patient having cardiovascular disease,
Orally administering 0.5 mg of colchicine to a human patient,
Wherein the method provides a peak concentration of colchicine (Cmax) in plasma in the range of about 0.5-5 ng / mL and a Cmax time to reach (Tmax) after a first dose of about 1.5-8 hours. 57. The method of claim 55, wherein the method further provides an area under the colchicine concentration curve in plasma from time 0 to time t in the range of about 4 - 20 ng-hr / mL (AUC0-t)
Wherein t is the last time point at which the concentration of colchicine in the plasma can be measured. 56. The method of claim 55 or 56, wherein the method further provides an area under the colchicine concentration curve in plasma (AUCO-infinity) from 0 h to infinity in the range of about 4 - 20 ng-hr / . 57. The method of any one of claims 55 to 57, wherein the method comprises measuring an area under the colchicine concentration curve (AUC0-t) in plasma from time 0 to time t in the range of about 4 - 20 ng-hr / Additional area under the colchicine concentration curve in plasma (AUCO-∞) from 0 h to infinity in the range of 20 ng-hr / mL,
Wherein t is the last time point at which the concentration of colchicine in the plasma can be measured. 58. The method of any one of claims 55 to 58 wherein said oral administration comprises administration of one or more dosage forms comprising 0.5 mg each of colchicin. 60. The method of any one of claims 55 to 59, wherein the dosage form is tablet. 60. The method of any one of claims 55 to 60 wherein the tablet is a sustained-release tablet. A method of treating a patient having cardiovascular disease,
Administering colchicine to said patient at a defined daily dose based on the patient's body weight,
Wherein said defined daily dose of colchicine is from about 50% to about 300% of 0.5 mg / day, based on a patient having a body weight of about 70 kg. 3. A formulation as claimed in claim 1 or 2 wherein the formulation releases at least about 80% of the colchicine in the test tube between about 1.5 and about 3.5 hours.

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